Oral Complications of Chemotherapy and Head/Neck Radiation (PDQ®): Supportive care - Health Professional Information [NCI]

Overview

Aggressive treatment of malignant disease may produce unavoidable toxicities to normal cells. The mucosal lining of the gastrointestinal tract, including the oral mucosa, is a prime target for treatment-related toxicity by virtue of its rapid rate of cell turnover. The oral cavity is highly susceptible to direct and indirect toxic effects of cancer chemotherapy and ionizing radiation.[1] This risk results from multiple factors, including high rates of cellular turnover for the lining mucosa, a diverse and complex microflora, and trauma to oral tissues during normal oral function.[2] Although changes in soft tissue structures within the oral cavity presumably reflect the changes that occur throughout the gastrointestinal tract, this summary focuses on oral complications of antineoplastic drugs and radiation therapies.

It is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. A multidisciplinary approach is warranted because the medical complexity of these patients affects dental treatment planning, prioritization, and timing of dental care. In addition, selected cancer patients (e.g., status posttreatment with high-dose head-and-neck radiation) are often at lifelong risk for serious complications such as osteoradionecrosis of the mandible. Thus, a multidisciplinary oncology team that includes oncologists, oncology nurses, and dental generalists and specialists as well as dental hygienists, social workers, dieticians, and related health professionals can often achieve highly effective preventive and therapeutic outcomes relative to oral complications in these patients.

While oral complications may mimic selected systemic disorders, unique oral toxicities emerge in the context of specific oral anatomic structures and their functions.

Frequencies of oral complications vary by cancer therapy; estimates are included in Table 1.

The most common oral complications related to cancer therapies are mucositis, infection, salivary gland dysfunction, taste dysfunction, and pain. These complications can lead to secondary complications such as dehydration, dysgeusia, and malnutrition. In myelosuppressed cancer patients, the oral cavity can also be a source of systemic infection. Radiation of the head and neck can irreversibly injure oral mucosa, vasculature, muscle, and bone, resulting in xerostomia, rampant dental caries, trismus, soft tissue necrosis, and osteonecrosis.

Severe oral toxicities can compromise delivery of optimal cancer therapy protocols. For example, dose reduction or treatment schedule modifications may be necessary to allow for resolution of oral lesions. In cases of severe oral morbidity, the patient may no longer be able to continue cancer therapy; treatment is then usually discontinued. These disruptions in dosing caused by oral complications can directly affect patient survivorship.

Management of oral complications of cancer therapy includes identification of high-risk populations, patient education, initiation of pretreatment interventions, and timely management of lesions. Assessment of oral status and stabilization of oral disease before cancer therapy are critical to overall patient care. Care should be both preventive and therapeutic to minimize risk for oral and associated systemic complications.

Future research targeted at developing technologies is needed to:

• Reduce incidence and severity of oral mucositis.
• Improve infection management.
• Protect salivary gland function.
• Minimize risk of chronic sequelae.

Development of new technologies to prevent cancer therapy-induced complications, especially oral mucositis, could substantially reduce the risk of oral pain, oral and systemic infections, and number of days in the hospital; and could improve quality of life and reduce health care costs. New technologies could also provide a setting in which novel classes of chemotherapeutic drugs, used at increased doses, could lead to enhanced cancer cure rates and durability of disease remission.

As has been noted, it is essential that a multidisciplinary approach be used for oral management of the cancer patient before, during, and after cancer treatment. This collaboration is pivotally important for the advancement of basic, clinical, and translational research associated with oral complications of current and emerging cancer therapies. The pathobiologic complexity of oral complications and the ever-expanding science base of clinical management require this comprehensive interdisciplinary approach.

In this summary, unless otherwise stated, evidence and practice issues as they relate to adults are discussed. The evidence and application to practice related to children may differ significantly from information related to adults. When specific information about the care of children is available, it is summarized under its own heading.

References:

1. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
2. Keefe DM, Schubert MM, Elting LS, et al.: Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109 (5): 820-31, 2007.
3. Migliorati CA, Woo SB, Hewson I, et al.: A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 18 (8): 1099-106, 2010.
4. Hovan AJ, Williams PM, Stevenson-Moore P, et al.: A systematic review of dysgeusia induced by cancer therapies. Support Care Cancer 18 (8): 1081-7, 2010.
5. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010.
6. Elad S, Zadik Y, Hewson I, et al.: A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea. Support Care Cancer 18 (8): 993-1006, 2010.
7. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010.
8. Peterson DE, Doerr W, Hovan A, et al.: Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 18 (8): 1089-98, 2010.
9. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al.: A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer 18 (8): 1033-8, 2010.
10. Epstein JB, Hong C, Logan RM, et al.: A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 18 (8): 1023-31, 2010.
11. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010.

Etiopathogenesis

Oral complications associated with cancer chemotherapy and radiation result from complex interactions among multiple factors. The most prominent contributors are direct lethal and sublethal damage to oral tissues, attenuation of immune and other protective systems, and interference with normal healing. Principal causes can be attributed to both direct stomatotoxicity and indirect stomatotoxicity. Direct toxicities are initiated via primary injury to oral tissues. Indirect toxicities are caused by nonoral toxicities that secondarily affect the oral cavity, including the following:

• Myelosuppression.
• Loss of tissue-based immune cells.
• Loss of protective salivary constituents.

Understanding of mechanisms associated with oral complications continues to increase. Unfortunately, there are no universally effective agents or protocols to prevent toxicity. Elimination of preexisting dental/periapical, periodontal, and mucosal infections; institution of comprehensive oral hygiene protocols during therapy; and reduction of other factors that may compromise oral mucosal integrity (e.g., physical trauma to oral tissues) can reduce frequency and severity of oral complications in cancer patients (refer to the Oral and Dental Management Before Cancer Therapy and the Oral and Dental Management After Cancer Therapy sections of this summary for further information).[1]

Complications can be acute (developing during therapy) or chronic (developing months to years after therapy). In general, cancer chemotherapy causes acute toxicities that resolve following discontinuation of therapy and recovery of damaged tissues. In contrast, radiation protocols typically cause not only acute oral toxicities, but induce permanent tissue damage that result in lifelong risk for the patient.

Chemotherapy-induced Complications

Risk factors for oral complications (see Table 2) derive from both direct damage to oral tissues secondary to chemotherapy and indirect damage due to regional or systemic toxicity. For example, therapy-related toxicity to oral mucosa can be exacerbated by colonizing oral microflora when local and systemic immune function is concurrently compromised. Frequency and severity of oral complications are directly related to extent and type of systemic compromise.

Ulcerative oral mucositis occurs in approximately 40% of patients receiving chemotherapy. In approximately 50% of these patients, the lesions are severe and require medical intervention including modification of their cytotoxic cancer therapy. Normal oral mucosal epithelium is estimated to undergo complete replacement every 9 to 16 days. Intensive chemotherapy can cause ulcerative mucositis that initially emerges approximately 2 weeks after initiation of high-dose chemotherapy.[2,3,4]

Chemotherapy directly impairs replication of basal epithelial cells; other factors, including proinflammatory cytokines and metabolic products of bacteria, may also play a role. The labial mucosa, buccal mucosa, tongue, floor of mouth, and soft palate are more severely affected by chemotherapy than are the attached, heavily keratinized tissues such as the hard palate and gingiva; this may be caused by relative rate of epithelial cell turnover among high-risk versus low-risk oral mucosal tissues. Topical cryotherapy may ameliorate mucositis caused by agents such as 5-fluorouracil (5-FU) by reducing vascular delivery of these toxic agents to replicating oral epithelium.[5]

It is difficult to predict whether a patient will develop mucositis strictly on the basis of the classes of drugs that are administered. Several drugs are associated with a propensity to damage oral mucosa:

• Methotrexate.
• Doxorubicin.
• 5-FU.
• Busulfan.
• Bleomycin.
• The platinum coordination complexes, including cisplatin and carboplatin.
• Mammalian target of rapamycin (mTOR) inhibitors (a new class of targeted cancer therapeutic agents).[6,7]

Anecdotal evidence suggests that patients who experience mucositis with a specific chemotherapy regimen during the first cycle will typically develop comparable mucositis during subsequent courses of that regimen.

Other oral complications typically include infections of the mucosa, dentition/periapices, and periodontium. Prevalence of these infections has been substantiated in multiple studies.[8,9,10,11] Specific criteria for determining risk of infectious flare during myelosuppression have not been developed. Guidelines for assessment primarily address both degree of severity of the chronic lesion and whether acute symptoms have recently (i.e., <90 days) developed. However, chronic asymptomatic periodontitis may also represent a focus for systemic infectious complications since bacteria, bacterial cell wall substances, and inflammatory cytokines may translocate into the circulation via ulcerated pocket epithelium.[10] In addition, poor oral hygiene and periodontitis seem to increase the prevalence of pulmonary infections in high-risk patients.[12]

Resolution of oral toxicity, including mucositis and infection, generally coincides with granulocyte recovery. This relationship may be temporally but not causally related. For example, oral mucosal healing in hematopoietic stem cell transplantation patients is only partially dependent on rate of engraftment, especially neutrophils.

Head/Neck Radiation-induced Complications

Head and neck radiation can cause a wide spectrum of oral complications (refer to the list of Oral Complications of Radiation Therapy). Ulcerative oral mucositis is a virtually universal toxicity resulting from this treatment; there are clinically significant similarities as well as differences compared with oral mucositis caused by chemotherapy.[2] In addition, oral mucosal toxicity can be increased by use of head and neck radiation together with concurrent chemotherapy.

Head and neck radiation can also induce damage that results in permanent dysfunction of vasculature, connective tissue, salivary glands, muscle, and bone. Loss of bone vitality occurs:

• Secondary to injury to osteocytes, osteoblasts, and osteoclasts.
• From a relative hypoxia due to reduction in vascular supply.

These changes can lead to soft tissue necrosis and osteonecrosis that result in bone exposure, secondary infection, and severe pain.[11]

Oral Complications of Radiation Therapy

• Acute complications:
  • Oral mucositis.
  • Infection:
    • Fungal.
    • Bacterial.
  • Salivary gland dysfunction:
    • Sialadenitis.
    • Xerostomia.
  • Taste dysfunction.
• Chronic complications:
  • Mucosal fibrosis and atrophy.
  • Xerostomia.
  • Dental caries.
  • Soft tissue necrosis.
  • Osteonecrosis.
  • Taste dysfunction:
    • Dysgeusia.
    • Ageusia.
  • Muscular/cutaneous fibrosis.
  • Infections:
    • Fungal.
    • Bacterial.

Unlike chemotherapy, however, radiation damage is anatomically site-specific; toxicity is localized to irradiated tissue volumes. Degree of damage depends on treatment regimen-related factors, including type of radiation utilized, total dose administered, and field size/fractionation. Radiation-induced damage also differs from chemotherapy-induced changes in that irradiated tissue tends to manifest permanent damage that places the patient at continual risk for oral sequelae. The oral tissues are thus more easily damaged by subsequent toxic drug or radiation exposure, and normal physiologic repair mechanisms are compromised as a result of permanent cellular damage.

References:

1. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.
2. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.
3. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
4. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
5. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993.
6. Pilotte AP, Hohos MB, Polson KM, et al.: Managing stomatitis in patients treated with Mammalian target of rapamycin inhibitors. Clin J Oncol Nurs 15 (5): E83-9, 2011.
7. de Oliveira MA, Martins E Martins F, Wang Q, et al.: Clinical presentation and management of mTOR inhibitor-associated stomatitis. Oral Oncol 47 (10): 998-1003, 2011.
8. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001.
9. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002.
10. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002.
11. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.
12. Paju S, Scannapieco FA: Oral biofilms, periodontitis, and pulmonary infections. Oral Dis 13 (6): 508-12, 2007.

Oral and Dental Management Before Cancer Therapy

Poor oral health has been associated with increased incidence and severity of oral complications in cancer patients, hence the adoption of an aggressive approach to stabilizing oral care before treatment.[1,2] Primary preventive measures such as appropriate nutritional intake, effective oral hygiene practices, and early detection of oral lesions are important pretreatment interventions.

There is no universally accepted pre-cancer therapy dental protocol because of the lack of clinical trials evaluating the efficacy of a specific protocol. A systematic review of the literature revealed two articles on oral care protocols prior to cancer therapy.[3] One study examined the benefits of a minimal intervention pre-cancer therapy (mostly chemotherapy) dental protocol, and the other examined the impact of an intensive preventive protocol on patients undergoing chemotherapy. Both studies had several flaws, including small sample size or the lack of comparison groups.[3]

The involvement of a dental team experienced with oral oncology may reduce the risk of oral complications via either direct examination of the patient or in consultation with the community-based dentist. The evaluation should occur as early as possible before treatment.[4,5] The examination allows the dentist to determine the status of the oral cavity before cancer treatment begins and to initiate necessary interventions that may reduce oral complications during and after that therapy. Ideally, this examination should be performed at least 1 month before the start of cancer treatment to permit adequate healing from any required invasive oral procedures. A program of oral hygiene should be initiated, with emphasis on maximizing patient compliance on a continuing basis.

Chemotherapy Patients

Oral evaluation and management of patients scheduled to undergo myeloablative chemotherapy should occur as early as possible before initiation of therapy (refer to the list on Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation). To maximize outcomes, the oncology team should clearly advise the dentist as to the patient's medical status and oncology treatment plan. In turn, the dental team should delineate and communicate a plan of care for oral disease management before, during, and after cancer therapy.[5]

Oral Disease Stabilization Before Chemotherapy and/or Hematopoietic Stem Cell Transplantation

• Data provided by oncology team to dental providers:
  • Underlying disease:
    • Cancer: type, stage, prognosis.
    • Aplastic anemia status, complete blood count (CBC).
    • Other.
  • Type of transplant:
    • Autologous.
    • Allogeneic donor types:
      • Matched related and unrelated.
      • Mismatched related.
    • Mismatched unrelated.
    • Syngeneic.
  • Hematopoietic stem cell source:
    • Bone marrow.
    • Peripheral stem cells.
    • Cord blood stem cells.
  • Conditioning regimen:
    • Myeloablative.
    • Reduced-intensity conditioning (including nonmyeloablative regimens).
  • Planned date of transplant.
  • Conditioning regimen:
    • Chemotherapy.
    • Total-body irradiation.
    • Radioactive antibodies.
  • Current hematologic status and immunologic status.
  • Present medications.
  • Other medical considerations:
    • Cardiac disease (including murmurs).
    • Pulmonary disease.
    • Indwelling venous access line.
    • Coagulation status.
    • Splenectomy.
• Data provided by dental providers to oncology team:
  • Dental caries (number of teeth and severity, including designation of number of teeth that should be treated before cancer treatment begins).
  • Endodontic disease:
    • Teeth with pulpal infection.
    • Teeth with periapical infection.
  • Periodontal disease status.
  • Number of teeth requiring extraction.
  • Other urgent care required.
  • Time necessary to complete stabilization of oral disease.

The overall goal is to complete a comprehensive oral care plan that eliminates or stabilizes oral disease that could otherwise produce complications during or following chemotherapy. Achieving this goal will most likely reduce risk of oral toxicities with resultant reduced risk for systemic sequelae, reduced cost of patient care, and enhanced quality of life. If the patient is unable to receive the medically necessary oral care in the community, the oncology team should assume responsibility for oral management.

It is important to realize that dental treatment plans need to be realistic relative to type and extent of dental disease and how long it could be before resumption of routine dental care. For example, teeth with minor caries may not need restoration before cancer treatment begins, especially if more conservative disease stabilization strategies can be used (e.g., aggressive topical fluoride protocols, temporary restorations, or dental sealants).

Specific interventions are directed to:

• Mucosal lesions.
• Dental caries and endodontic disease.
• Periodontal disease.
• Ill-fitting dentures.
• Orthodontic appliances.
• Temporomandibular dysfunction.
• Salivary abnormalities.

Guidelines for dental extractions, endodontic management, and related interventions (see Table 3) can be used as appropriate.[6,7] Antibiotic prophylaxis prior to invasive oral procedures may be warranted in the context of central venous catheters; the current American Heart Association (AHA) protocol for infective endocarditis and oral procedures is frequently used for these patients.

Assessment of Hematopoietic Stem Cell Transplant Patients

Stages of assessment have been described relative to the hematopoietic stem cell transplant patient (see Table 4).[5] This model provides a useful classification for neutropenic cancer patients in general. Type, timing, and severity of oral complications represent the interaction of local and systemic factors that culminate in clinical expression of disease. Correlating oral status with systemic condition of the patient is thus critically important.

Selected conditioning regimens characterized by reduced intensity for myelosuppression have been used in patients. These regimens have generally been noted to significantly reduce the severity of oral complications early posttransplant, especially for mucositis and infection risk. The guidelines listed in Table 4 can be adjusted to reflect these varying degrees of risk, based on the specific conditioning regimen to be used.

Phase I: Before Chemotherapy

Oral complications are related to current systemic and oral health, oral manifestations of underlying disease, and oral complications of recent cancer or other medical therapy. During this period, oral trauma and clinically significant infections, including dental caries, periodontal disease, and pulpal infection, should be eliminated. Additionally, patients should be educated relative to the range and management of oral complications that may occur during subsequent phases. Baseline oral hygiene instructions should be provided. It is especially important to note whether patients have been treated with bisphosphonates (e.g., patients with multiple myeloma) and to plan their care accordingly.

Phase II: Neutropenic Phase

Oral complications arise primarily from direct and indirect stomatotoxicities associated with high-dose chemotherapy or chemoradiotherapy and their sequelae. Mucositis, xerostomia, and those lesions related to myelosuppression, thrombocytopenia, and anemia predominate. This phase is typically the period of high prevalence and severity of oral complications.

Oral mucositis usually begins 7 to 10 days after initiation of cytotoxic therapy and remains present for approximately 2 weeks after cessation of that therapy. Viral, fungal, and bacterial infections may arise, with incidence dependent on the use of prophylactic regimens, oral status prior to chemotherapy, and duration/severity of neutropenia. Frequency of infection declines upon resolution of mucositis and regeneration of neutrophils. This phenomenon appears to be more a temporal relation than a causative one, based on the predominant evidence. Despite the initial marrow recovery, however, the patient may remain at risk for infection, depending on status of overall immune reconstitution.

Salivary gland hypofunction/xerostomia secondary to anticholinergic drugs and taste dysfunction is initially detected in this phase; the toxicity typically resolves within 2 to 3 months.

In allogeneic transplant patients, while uncommon, hyperacute graft-versus-host disease (GVHD) can occur and can result in significant oral mucosal inflammation and breakdown that can complicate the oral course for patients. Clinical presentation will often not be sufficiently distinct to diagnosis this lesion. The clinical assessment is typically based on the patient experiencing more-severe-than-expected mucositis that will often not heal within the time line for mucosal recovery associated with oral mucositis caused by chemotherapy.

Phase III: Hematopoietic Recovery

Frequency and severity of acute oral complications typically begin to decrease approximately 3 to 4 weeks after cessation of chemotherapy. Healing of ulcerative oral mucositis in the setting of marrow regeneration contributes to this dynamic. Although immune reconstitution is developing, oral mucosal immune defenses may not be optimal. Generally stated, immune reconstitution will take between 6 and 9 months for autologous transplant patients and between 9 and 12 months for allogeneic transplant patients not developing chronic GVHD. Thus, the patient remains at risk for selected infection, including candidal and herpes simplex virus infections.

Mucosal bacterial infections during this phase occur less frequently unless engraftment is delayed or the patient has acute GVHD or is receiving GVHD therapy. Most centers will use systemic infection prophylaxis throughout this period (and, in many instances, longer) to reduce the risk of infections in general, a practice that positively influences the rate and severity of both systemic and local oral infections.

The hematopoietic stem cell transplant patient represents a unique cohort at this point. For example, risk for acute oral GVHD typically emerges during this time in allogeneic graft recipients.

Phase IV: Immune Reconstitution/Recovery from Systemic Toxicity

Oral lesions are principally related to chronic conditioning regimen-associated (chemotherapy with or without radiation therapy) toxicity and, in the allogeneic patient, GVHD. Late viral infections and xerostomia predominate. Mucosal bacterial infections are infrequent unless the patient remains neutropenic or has severe chronic GVHD.

Risk exists for graft failure, cancer relapse, and second malignancies. The hematopoietic stem cell transplant patient may develop oral manifestations of chronic GVHD during this period.

Phase V: Long-term Survival

Long-term survivors of cancer treated with high-dose chemotherapy alone or chemoradiotherapy will generally have few significant permanent oral complications.

Risk for radiation-induced chronic complications is related to the total dose and schedule of radiation therapy. Regimens that incorporate total body irradiation may result in permanent salivary gland hypofunction/xerostomia,[8] which is the most frequently reported late oral complication. Permanent salivary gland dysfunction can occur in autologous transplant patients in addition to nonautologous recipients. Other significant complications include craniofacial growth and developmental abnormalities in pediatric patients, and emergence of second malignancies of the head/neck region.

References:

1. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.
2. Epstein JB: Infection prevention in bone marrow transplantation and radiation patients. NCI Monogr (9): 73-85, 1990.
3. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010.
4. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
5. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
6. Williford SK, Salisbury PL 3rd, Peacock JE Jr, et al.: The safety of dental extractions in patients with hematologic malignancies. J Clin Oncol 7 (6): 798-802, 1989.
7. Overholser CD, Peterson DE, Bergman SA, et al.: Dental extractions in patients with acute nonlymphocytic leukemia. J Oral Maxillofac Surg 40 (5): 296-8, 1982.
8. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010.

Oral and Dental Management After Cancer Therapy

Routine systematic oral hygiene is important for reducing incidence and severity of oral sequelae of cancer therapy. The patient must be informed of the rationale for the oral hygiene program as well as the potential side effects of cancer chemotherapy and radiation therapy. Effective oral hygiene is important throughout cancer treatment, with emphasis on oral hygiene beginning before treatment starts.[1]

Management of patients undergoing either high-dose chemotherapy or upper-mantle radiation share selected common principles. These principles are based on baseline oral care (refer to the list of suggestions for Routine Oral Hygiene Care) and reduction of physical trauma to oral mucosa (refer to the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy).

Routine Oral Hygiene Care

• Toothbrushing. Electric and ultrasonic toothbrushes are acceptable if the patient is capable of using them without causing trauma.
• Soft nylon-bristled brush (two to three rows).
  • Brush 2 to 3 times daily with Bass sulcular scrub method.
  • Rinse frequently.
  • Foam toothbrushes:
    • Use only when use of a regular toothbrush is not feasible.
    • Use with antimicrobial rinses when routine brushing and flossing are not possible.
    • Brush teeth 2 to 3 times a day.
    • Rinse frequently.
• Dentifrice:
  • Patient preference, as tolerated.
    • (Note: Non-mint-flavored products are typically better tolerated than mint-flavored products when oral mucositis or oral graft-versus-host disease [GVHD] is present).
  • Fluoride recommended.
  • Use 0.9% saline or water if toothpaste causes irritation.
• Flossing:
  • Once daily.
  • Atraumatic technique with modifications as needed.
• Bland rinses:
  • Varieties:
    • 0.9% saline.
    • Sodium bicarbonate solution.
    • 0.9% saline plus sodium bicarbonate solution.
  • Use 8 to 12 oz of rinse, hold a mouthful, and expectorate until total volume is used; repeat every 2 to 4 hours or as needed to ameliorate discomfort.
• Fluoride:
  • 1.1% neutral sodium fluoride gel.
  • 0.4% stannous fluoride gel.
  • Brush on gel for 2 to 3 minutes.
  • Expectorate and rinse mouth gently.
  • Apply once a day.
• Topical antimicrobial rinses:
  • 0.12% to 0.2% chlorhexidine oral rinse for management of acute gingival lesions.
  • Povidone iodine oral rinse.
  • Rinse, hold 1 to 2 minutes, and expectorate.
  • Repeat 2 to 4 times a day, depending on severity of periodontal disease.

Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy[1]

• Minimize denture use during first 3 weeks posttransplant.
  • Wear dentures only when eating.
  • Discontinue use at all other times.
• Clean twice a day with a soft brush and rinse well.
• Soak in antimicrobial solutions when not being worn.
• Perform routine oral mucosal care procedures 3 to 4 times a day with the oral appliances out of the mouth.
• Leave appliances out of mouth when sleeping and during periods of significant mouth soreness.
• Dentures may be used to hold medications needed for oral care (e.g., antifungals).
• Discontinue use of removable appliances until oral mucositis has healed.
• Remove orthodontic appliances (e.g., brackets, wires, retainers) before conditioning.

Considerable variation exists across institutions relative to specific nonmedicated approaches to baseline oral care, given limited published evidence. Most nonmedicated oral care protocols use topical, frequent (every 4-6 hours) rinsing with 0.9% saline. Additional interventions include dental brushing with toothpaste, dental flossing, ice chips, and sodium bicarbonate rinses. Patient compliance with these agents can be maximized by comprehensive overseeing by the health care professional.

Patients using removable dental prostheses or orthodontic appliances have risk of mucosal injury or infection. This risk can be eliminated or substantially reduced prior to high-dose cancer therapy. (Refer to the list of Guidelines for Management of Dentures and Orthodontic Appliances in Patients Receiving High-Dose Cancer Therapy.)

Dental brushing and flossing represent simple, cost-effective approaches to bacterial dental plaque control. This strategy is designed to reduce risk of oral soft tissue infection during myeloablation. Oncology teams at some centers promote their use, while teams at other centers have patients discontinue brushing and flossing when peripheral blood components decrease below defined thresholds (e.g., platelets <30,000/mm³). There is no comprehensive evidence base regarding the optimal approach. Many centers adopt the strategy that the benefits of properly performed dental brushing and flossing in reducing risk of gingival infection outweigh the risks.

Periodontal infection (gingivitis and periodontitis) increases risk for oral bleeding; healthy tissues should not bleed. Discontinuing dental brushing and flossing can increase risk for gingival bleeding, oral infection, and bacteremia. Risk for gingival bleeding and infection, therefore, is reduced by eliminating gingival infection before therapy and promoting oral health daily by removing bacterial plaque with gentle debridement with a soft or ultra-soft toothbrush during therapy. Mechanical plaque control not only promotes gingival health, but it also may decrease risk of exacerbation of oral mucositis secondary to microbial colonization of damaged mucosal surfaces.

Dental brushing and flossing should be performed daily under the supervision of professional staff:

• A soft nylon-bristled toothbrush should be used 2 to 3 times a day with techniques that specifically maintain the gingival portion of the tooth and periodontal sulcus, keeping them free of bacterial plaque.
• Rinsing the toothbrush in hot water every 15 to 30 seconds during brushing will soften the brush and reduce risk for trauma.
• Oral rinsing with water or saline 3 to 4 times while brushing will further aid in removal of dental plaque dislodged by brushing.
• Rinses containing alcohol should be avoided.
• A toothpaste with a relatively neutral taste should be considered because the flavoring agents in toothpaste can irritate oral soft tissues.
• Brushes should be air-dried between uses.
• While disinfectants have been suggested, their routine use to clean brushes has not been proven of value.
• Ultrasonic toothbrushes may be substituted for manual brushes if patients are properly trained in their use.

Patients skilled at flossing without traumatizing gingival tissues may continue flossing throughout chemotherapy administration. Flossing allows for interproximal removal of dental bacterial plaque and thus promotes gingival health. As with dental brushing, this intervention should be performed under the supervision of professional staff to ensure its safe administration.

The oral cavity should be cleaned after meals:

• If xerostomia is present, plaque and food debris may accumulate secondary to reduced salivary function, and more frequent hygiene may be necessary.
• Dentures need to be cleaned with denture cleanser every day and should be brushed and rinsed after meals.
• Rinsing the oral cavity may not be sufficient for thorough cleansing of the oral tissues; mechanical plaque removal is often necessary.
• Care must be exerted in the use of the varied mechanical hygiene aids that are available; dental floss, interproximal brushes, and wooden wedges can injure oral tissues rendered fragile by chemotherapy.
• Toothettes have limited ability to cleanse the dentition; however, they may be useful for cleaning maxillary/mandibular alveolar ridges of edentulous areas, palate, and tongue.

Preventing dryness of the lips to reduce risk for tissue injury is important. Mouth breathing and/or xerostomia secondary to anticholinergic medications used for nausea management can induce the condition. GVHD of the lips can also contribute to dry lips in allogeneic transplant patients. Lip care products containing petroleum-based oils and waxes can be useful. Lanolin-based creams and ointments may be more effective in moisturizing/lubricating the lips and thus protecting against trauma.

References:

1. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.

Oral Mucositis

The terms oral mucositis and stomatitis are often used interchangeably at the clinical level, but they do not reflect identical processes.

Oral Mucositis:

• Describes inflammation of oral mucosa resulting from chemotherapeutic agents or ionizing radiation.[1,2,3]
• Typically manifests as erythema or ulcerations.
• May be exacerbated by local factors.

Stomatitis:

• Refers to any inflammatory condition of oral tissue, including mucosa, dentition/periapices, and periodontium.
• Includes infections of oral tissues as well as mucositis.

Risk of oral mucositis has historically been characterized by treatment-based and patient-based variables.[4] The current model of oral mucositis involves a complex trajectory of molecular, cellular, and tissue-based changes. There is increasing evidence of genetic governance of this injury,[5,6,7,8] characterized in part by upregulation of nuclear factor kappa beta and inflammatory cytokines (e.g., tumor necrosis factor-alpha) and interleukin-1 in addition to epithelial basal cell injury. Comprehensive knowledge of the molecular-based causation of the lesion has contributed to targeted drug development for clinical use.[9] The pipeline of new drugs in development (e.g., recombinant human intestinal trefoil factor [10] may lead to strategic new advances in the ability of clinicians to customize the prevention and treatment of oral mucositis in the future.[11]

Erythematous mucositis typically appears 7 to 10 days after initiation of high-dose cancer therapy. Clinicians should be alert to the potential for increased toxicity with escalating dose or treatment duration in clinical trials that demonstrate gastrointestinal mucosal toxicity. High-dose chemotherapy, such as that used in the treatment of leukemia and hematopoietic stem cell transplant regimens, may produce severe mucositis. Mucositis is self-limited when uncomplicated by infection and typically heals within 2 to 4 weeks after cessation of cytotoxic chemotherapy.

Systematic assessment of the oral cavity following treatment permits early identification of lesions.[12,13,14,15,16] Oral hygiene and other supportive care measures are important to minimizing the severity of the lesion.

In an effort to standardize measurements of mucosal integrity, oral assessment scales have been developed to grade the level of stomatitis by characterizing alterations in lips, tongue, mucous membranes, gingiva, teeth, pharynx, quality of saliva, and voice.[12,13,14] Specific instruments of assessment have been developed to evaluate the observable and functional dimensions of mucositis. These evaluative tools vary in complexity.

Chemoradiotherapy and Hematopoietic Stem Cell Transplantation Patients

Management of mucositis

Prophylactic measures and treatment options should be employed by practitioners for patients in the appropriate clinical settings. Specific recommendations for minimizing oral mucositis include the following:

• Good oral hygiene.
• Avoidance of spicy, acidic, hard, and hot foods and beverages.
• Use of mild-flavored toothpastes.
• Use of saline-peroxide mouthwashes 3 or 4 times per day.

Updated guidelines from the American Society of Clinical Oncology for the prevention and treatment of mucositis were published in 2007 [17] and include the following:

• Palifermin for oral mucositis associated with stem cell transplantation.
• Amifostine for radiation proctitis.
• Cryotherapy for high-dose-melphalan-induced mucositis.

Specific recommendations against specific practices include the following:

• No systemic glutamine for the prevention of gastrointestinal mucositis.
• No sucralfate or antibiotic lozenges for radiation-induced mucositis.
• No granulocyte-macrophage colony-stimulating factor mouthwashes.

Oral mucositis in hematopoietic stem cell transplantation patients produces clinically significant toxicities that require multiprofessional interventions.[18,19,20,21,22,23,24,25] The lesion can increase risk of systemic infection,[1] produce clinically significant pain,[26][Level of evidence: II] and promote oral hemorrhage. It can also compromise the upper airway such that endotracheal intubation is required. Use of total parenteral nutrition is often necessary because of the patient's inability to receive enteral nutrition.

Once mucositis has developed, its severity and the patient's hematologic status govern appropriate oral management. Meticulous oral hygiene and palliation of symptoms are essential. Some established guidelines for oral care include oral assessments twice daily for hospitalized patients and frequent oral care (minimum of every 4 hours and at bedtime) that increases in frequency as the severity of mucositis increases.

Oral care protocols generally include atraumatically cleansing the oral mucosa, maintaining lubrication of the lips and oral tissues, and relieving pain and inflammation. Several health professional organizations have produced evidence-based oral mucositis guidelines. These organizations include but are not limited to the following:

• Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology [17]
• National Comprehensive Cancer Network [27]
• European Society of Medical Oncology [11]
• European Oncology Nursing Society
• The Cochrane Collaboration [28,29]

In many cases, there is similarity in recommendations across the organizations. The Cochrane Collaboration, however, uses a meta-analysis approach and thus provides a unique context for purposes of guideline construction.

Palifermin (Kepivance), also known as keratinocyte growth factor-1, has been approved to decrease the incidence and duration of severe oral mucositis in patients with hematologic cancers undergoing conditioning with high-dose chemotherapy, with or without radiation therapy, followed by hematopoietic stem cell rescue.[9][Level of evidence: I] The standard dosing regimen is three daily doses before conditioning and three additional daily doses starting on day 0 (day of transplant). Palifermin has also been shown in a randomized, placebo-controlled trial to reduce the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy.[30][Level of evidence: I] In addition, a single dose of palifermin prevented severe oral mucositis in patients who had sarcoma and were receiving doxorubicin-based chemotherapy.[31][Level of evidence: I]

In two randomized, placebo-controlled trials conducted in head/neck cancer patients undergoing postoperative chemoradiotherapy and in patients receiving definitive chemoradiotherapy for locally advanced head/neck cancer, intravenous palifermin administered weekly for 8 weeks decreased severe oral mucositis,[32,33][Level of evidence: I] as graded by providers using standard toxicity assessments and during multicycle chemotherapy.[31] Patient-reported outcomes related to mouth and throat soreness and to treatment breaks or compliance were not significantly different between arms in either trial. In one study, opioid analgesic use was also not significantly different between arms.[33]

Evidence from several studies has supported the potential efficacy of low-level laser therapy in addition to oral care to decrease the duration of chemotherapy-induced oral mucositis in children.[34][Level of evidence: I][35][Level of evidence: I]

Mucositis Management

• Bland rinses:
  • 0.9% saline solution.
  • Sodium bicarbonate solution.
  • 0.9% saline/sodium bicarbonate solution.
• Topical anesthetics:
  • Lidocaine: viscous, ointments, sprays.
  • Benzocaine: sprays, gels.
  • 0.5% or 1.0% dyclonine hydrochloride (HCl).
  • Diphenhydramine solution.
• Mucosal coating agents:
  • Amphojel.
  • Kaopectate.
  • Hydroxypropyl methylcellulose film-forming agents (e.g., Zilactin).
  • Gelclair (approved by the U.S. Food and Drug Administration [FDA] as a device).
• Analgesics:
  • Benzydamine HCl topical rinse (not approved in the United States).
  • Opioid drugs: oral, intravenous (e.g., bolus, continuous infusion, patient-controlled analgesia [PCA]), patches, transmucosal.
• Growth factor (keratinocyte growth factor-1):
  • Palifermin (approved by the FDA in December 2004 to decrease the incidence and duration of severe oral mucositis in patients undergoing high-dose chemotherapy with or without radiation therapy followed by bone marrow transplant for hematologic cancers).

Management of oral mucositis via topical approaches should address efficacy, patient acceptance, and appropriate dosing. A stepped approach is typically used, with progression from one level to the next as follows:

• Bland rinses (e.g., 0.9% normal saline and/or sodium bicarbonate solutions).
• Mucosal coating agents (e.g., antacid solutions, kaolin solutions).
• Water-soluble lubricating agents, including artificial saliva for xerostomia.
• Topical anesthetics (e.g., viscous lidocaine, benzocaine sprays/gels, dyclonine rinses, diphenhydramine solutions).
• Cellulose film-forming agents for covering localized ulcerative lesions (e.g., hydroxypropyl cellulose).

Normal saline solution is prepared by adding approximately 1 tsp of table salt to 32 oz of water. The solution can be administered at room or refrigerated temperatures, depending on patient preference. The patient should rinse and swish approximately 1 tbsp, followed by expectoration; this can be repeated as often as necessary to maintain oral comfort. Sodium bicarbonate (1-2 tbsp/qt) can be added, if viscous saliva is present. Saline solution can enhance oral lubrication directly as well as by stimulating salivary glands to increase salivary flow.

A soft toothbrush that is replaced regularly should be used to maintain oral hygiene.[17] Foam-swab brushes do not effectively clean teeth and should not be considered a routine substitute for a soft nylon-bristled toothbrush; additionally, the rough sponge surface may irritate and damage the mucosal surfaces opposite the tooth surfaces being brushed.

On the basis of nonoral mucosa wound-healing studies, the repeated use of hydrogen peroxide rinses for daily preventive oral hygiene is not recommended, especially if mucositis is present, because of the potential for damage to fibroblasts and keratinocytes, which can cause delayed wound healing.[36,37,38,39] Using 3% hydrogen peroxide diluted 1:1 with water or normal saline to remove hemorrhagic debris may be helpful; however, this approach should only be used for 1 or 2 days because more extended use may impair timely healing of mucosal lesions associated with bleeding.[40]

Focal topical application of anesthetic agents is preferred over widespread oral topical administration, unless the patient requires more extensive pain relief. Products such as the following may provide relief:

• 2% viscous lidocaine
• Diphenhydramine solution
• One of the many extemporaneously prepared mixtures combining the following coating agents with topical anesthetics:
  • Milk of magnesia.
  • Kaolin with pectin suspension.
  • Mixtures of aluminum.
  • Magnesium hydroxide suspensions (many antacids).

The use of compounded topical anesthetic rinses should be considered carefully relative to the cost of compounding these products versus their actual efficacy.

Irrigation should be performed before topical medication is applied because removal of debris and saliva allows for better coating of oral tissues and prevents material from accumulating. Frequent rinsing cleans and lubricates tissues, prevents crusting, and palliates painful gingiva and mucosa.

Systemic analgesics should be administered when topical anesthetic strategies are not sufficient for clinical relief. Opiates are typically used;[26][Level of evidence: II] the combination of chronic indwelling venous catheters and computerized drug administration pumps to provide PCA has significantly increased the effectiveness of controlling severe mucositis pain while lowering the dose and side effects of narcotic analgesics. Nonsteroidal anti-inflammatory drugs that affect platelet adhesion and damage gastric mucosa are contraindicated, especially if thrombocytopenia is present.

Although mucositis continues to be one of the dose-limiting toxicities of fluorouracil (5-FU), cryotherapy may be an option for preventing oral mucositis. Because 5-FU has a short half-life (5-20 minutes), patients are instructed to swish ice chips in their mouths for 30 minutes, beginning 5 minutes before 5-FU is administered.[41][Level of evidence: I] Oral cryotherapy has been studied in patients receiving high-dose melphalan conditioning regimens used with transplantation;[42,43] further research is needed.

Many agents and protocols have been promoted for management or prevention of mucositis.[44,45,46] Although not adequately supported by controlled clinical trials, allopurinol mouthwash and vitamin E have been cited as agents that decrease the severity of mucositis. Prostaglandin E2 was not effective as a prophylaxis of oral mucositis following bone marrow transplant, although studies indicate possible efficacy when prostaglandin E2 is administered via a different dosing protocol.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for supportive and palliative care trials about mucositis that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.
2. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
3. Sonis ST, Elting LS, Keefe D, et al.: Perspectives on cancer therapy-induced mucosal injury: pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 100 (9 Suppl): 1995-2025, 2004.
4. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003.
5. Ezzeldin HH, Diasio RB: Predicting fluorouracil toxicity: can we finally do it? J Clin Oncol 26 (13): 2080-2, 2008.
6. Schwab M, Zanger UM, Marx C, et al.: Role of genetic and nongenetic factors for fluorouracil treatment-related severe toxicity: a prospective clinical trial by the German 5-FU Toxicity Study Group. J Clin Oncol 26 (13): 2131-8, 2008.
7. Werbrouck J, De Ruyck K, Duprez F, et al.: Acute normal tissue reactions in head-and-neck cancer patients treated with IMRT: influence of dose and association with genetic polymorphisms in DNA DSB repair genes. Int J Radiat Oncol Biol Phys 73 (4): 1187-95, 2009.
8. Hahn T, Zhelnova E, Sucheston L, et al.: A deletion polymorphism in glutathione-S-transferase mu (GSTM1) and/or theta (GSTT1) is associated with an increased risk of toxicity after autologous blood and marrow transplantation. Biol Blood Marrow Transplant 16 (6): 801-8, 2010.
9. Spielberger R, Stiff P, Bensinger W, et al.: Palifermin for oral mucositis after intensive therapy for hematologic cancers. N Engl J Med 351 (25): 2590-8, 2004.
10. Peterson DE, Barker NP, Akhmadullina LI, et al.: Phase II, randomized, double-blind, placebo-controlled study of recombinant human intestinal trefoil factor oral spray for prevention of oral mucositis in patients with colorectal cancer who are receiving fluorouracil-based chemotherapy. J Clin Oncol 27 (26): 4333-8, 2009.
11. Peterson DE, Bensadoun RJ, Roila F, et al.: Management of oral and gastrointestinal mucositis: ESMO clinical recommendations. Ann Oncol 20 (Suppl 4): 174-7, 2009.
12. Schubert MM, Williams BE, Lloid ME, et al.: Clinical assessment scale for the rating of oral mucosal changes associated with bone marrow transplantation. Development of an oral mucositis index. Cancer 69 (10): 2469-77, 1992.
13. Sonis ST, Eilers JP, Epstein JB, et al.: Validation of a new scoring system for the assessment of clinical trial research of oral mucositis induced by radiation or chemotherapy. Mucositis Study Group. Cancer 85 (10): 2103-13, 1999.
14. McGuire DB, Peterson DE, Muller S, et al.: The 20 item oral mucositis index: reliability and validity in bone marrow and stem cell transplant patients. Cancer Invest 20 (7-8): 893-903, 2002.
15. Larson PJ, Miaskowski C, MacPhail L, et al.: The PRO-SELF Mouth Aware program: an effective approach for reducing chemotherapy-induced mucositis. Cancer Nurs 21 (4): 263-8, 1998.
16. Schubert MM: Oro-pharyngeal mucositis. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 812-20.
17. Keefe DM, Schubert MM, Elting LS, et al.: Updated clinical practice guidelines for the prevention and treatment of mucositis. Cancer 109 (5): 820-31, 2007.
18. Elting LS, Cooksley C, Chambers M, et al.: The burdens of cancer therapy. Clinical and economic outcomes of chemotherapy-induced mucositis. Cancer 98 (7): 1531-9, 2003.
19. Elting LS, Cooksley CD, Chambers MS, et al.: Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 68 (4): 1110-20, 2007.
20. Lalla RV, Sonis ST, Peterson DE: Management of oral mucositis in patients who have cancer. Dent Clin North Am 52 (1): 61-77, viii, 2008.
21. Peterson DE, Lalla RV: Oral mucositis: the new paradigms. Curr Opin Oncol 22 (4): 318-22, 2010.
22. Rosenthal DI: Consequences of mucositis-induced treatment breaks and dose reductions on head and neck cancer treatment outcomes. J Support Oncol 5 (9 Suppl 4): 23-31, 2007.
23. Sonis ST, Oster G, Fuchs H, et al.: Oral mucositis and the clinical and economic outcomes of hematopoietic stem-cell transplantation. J Clin Oncol 19 (8): 2201-5, 2001.
24. Sonis ST: Regimen-related gastrointestinal toxicities in cancer patients. Curr Opin Support Palliat Care 4 (1): 26-30, 2010.
25. Trotti A, Bellm LA, Epstein JB, et al.: Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 66 (3): 253-62, 2003.
26. Pillitteri LC, Clark RE: Comparison of a patient-controlled analgesia system with continuous infusion for administration of diamorphine for mucositis. Bone Marrow Transplant 22 (5): 495-8, 1998.
27. Bensinger W, Schubert M, Ang KK, et al.: NCCN Task Force Report. prevention and management of mucositis in cancer care. J Natl Compr Canc Netw 6 (Suppl 1): S1-21; quiz S22-4, 2008.
28. Clarkson JE, Worthington HV, Furness S, et al.: Interventions for treating oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev (8): CD001973, 2010.
29. Worthington HV, Clarkson JE, Bryan G, et al.: Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database Syst Rev 12: CD000978, 2010.
30. Rosen LS, Abdi E, Davis ID, et al.: Palifermin reduces the incidence of oral mucositis in patients with metastatic colorectal cancer treated with fluorouracil-based chemotherapy. J Clin Oncol 24 (33): 5194-200, 2006.
31. Vadhan-Raj S, Trent J, Patel S, et al.: Single-dose palifermin prevents severe oral mucositis during multicycle chemotherapy in patients with cancer: a randomized trial. Ann Intern Med 153 (6): 358-67, 2010.
32. Henke M, Alfonsi M, Foa P, et al.: Palifermin decreases severe oral mucositis of patients undergoing postoperative radiochemotherapy for head and neck cancer: a randomized, placebo-controlled trial. J Clin Oncol 29 (20): 2815-20, 2011.
33. Le QT, Kim HE, Schneider CJ, et al.: Palifermin reduces severe mucositis in definitive chemoradiotherapy of locally advanced head and neck cancer: a randomized, placebo-controlled study. J Clin Oncol 29 (20): 2808-14, 2011.
34. Kuhn A, Porto FA, Miraglia P, et al.: Low-level infrared laser therapy in chemotherapy-induced oral mucositis: a randomized placebo-controlled trial in children. J Pediatr Hematol Oncol 31 (1): 33-7, 2009.
35. Schubert MM, Eduardo FP, Guthrie KA, et al.: A phase III randomized double-blind placebo-controlled clinical trial to determine the efficacy of low level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic cell transplantation. Support Care Cancer 15 (10): 1145-54, 2007.
36. National Institutes of Health Consensus Development Conference on Oral Complications of Cancer Therapies: Diagnosis, Prevention, and Treatment. Bethesda, Maryland, April 17-19, 1989. NCI Monogr (9): 1-184, 1990.
37. Bavier AR: Nursing management of acute oral complications of cancer. NCI Monogr (9): 123-8, 1990.
38. Takahashi A, Aoshiba K, Nagai A: Apoptosis of wound fibroblasts induced by oxidative stress. Exp Lung Res 28 (4): 275-84, 2002.
39. Bennett LL, Rosenblum RS, Perlov C, et al.: An in vivo comparison of topical agents on wound repair. Plast Reconstr Surg 108 (3): 675-87, 2001.
40. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
41. Rocke LK, Loprinzi CL, Lee JK, et al.: A randomized clinical trial of two different durations of oral cryotherapy for prevention of 5-fluorouracil-related stomatitis. Cancer 72 (7): 2234-8, 1993.
42. Mori T, Yamazaki R, Aisa Y, et al.: Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients. Support Care Cancer 14 (4): 392-5, 2006.
43. Ohbayashi Y, Imataki O, Ohnishi H, et al.: Multivariate analysis of factors influencing oral mucositis in allogeneic hematopoietic stem cell transplantation. Ann Hematol 87 (10): 837-45, 2008.
44. Lugliè PF, Mura G, Mura A, et al.: [Prevention of periodontopathy and oral mucositis during antineoplastic chemotherapy. Clinical study] Minerva Stomatol 51 (6): 231-9, 2002.
45. Cheng KK, Molassiotis A, Chang AM, et al.: Evaluation of an oral care protocol intervention in the prevention of chemotherapy-induced oral mucositis in paediatric cancer patients. Eur J Cancer 37 (16): 2056-63, 2001.
46. Wardley AM, Jayson GC, Swindell R, et al.: Prospective evaluation of oral mucositis in patients receiving myeloablative conditioning regimens and haemopoietic progenitor rescue. Br J Haematol 110 (2): 292-9, 2000.

Orofacial Pain in Cancer Patients

Pain in cancer patients may arise from onset of the disease through survivorship and may be:[1]

• Caused by the malignant disease.
• Caused by acute or chronic complications of cancer therapy.
• Coincidental and unrelated to the cancer.

Cancer pain causes increased morbidity, reduced performance status, increased anxiety and depression, and diminished quality of life (QOL). Dimensions of acute and chronic pain include the following:

• Sensory
• Physiologic
• Affective
• Cognitive
• Behavioral
• Sociocultural

Management of head and neck pain and oral pain may be particularly challenging because eating, speech, swallowing, and other motor functions of the head and neck and oropharynx are constant pain triggers.

Orofacial Pain due to Cancer

Acute and chronic pain in cancer can result from several factors, including the following:

• Pain due to malignant disease:
  • Local/regional cancer.
  • Oral involvement in systemic/hematopoietic cancer.
  • Metastatic disease.
• Pain due to treatment:
  • Surgery.
  • Radiation.
  • Chemotherapy.
• Pain unrelated to malignancy.

Pain at diagnosis is often low intensity but typically becomes more frequent and severe with advancing disease. Cancer pain may be caused by local and distant tumor effects. Direct invasion by cancer may cause pain and may result from inflammatory and neuropathic mechanisms. Effective prevention and management of pain in cancer requires knowledge of the factors and mechanisms involved.

It is estimated that 45% to 80% of all cancer patients have inadequate pain management. Seventy-five percent to 90% of patients with terminal or advanced cancer may have pain. Pain may be present in up to 85% of patients with head and neck cancers (HNCs) at diagnosis.

Orofacial pain associated with cancer management is a well-recognized adverse effect of treatment. Pain due to oral mucositis is the most frequently reported patient-related complaint during cancer therapy. Severe and painful mucositis is associated with additional hospital admissions and prolonged periods in hospital, leading to delayed, interrupted, or altered cancer therapy protocols that may affect prognosis, QOL, and cost of care. Graft-versus-host disease (GVHD) is a common complication of allogeneic hematopoietic cell transplant (HCT), occurring in 25% to 70% of patients; oral lesions are often painful.

In addition to HNCs, oral manifestations of leukemia and lymphoma may cause pain and loss of function. Lymphomas and leukemias may induce pain by infiltration of pain-sensitive structures and if secondary oral infection occurs. Multiple myeloma frequently presents with pain and, when associated with teeth, presents a diagnostic challenge. Intracranial malignancies may give rise to orofacial pain and headache. Even in diagnosed cancer patients, the prediction of intracranial metastases with new or changed headache is difficult.

Pain may present similarly to classical trigeminal neuralgia. Jaw pain may be caused by metastatic cancer, and tumors arising from the breast, prostate, thyroid, lung, and kidney have a propensity to spread to bone in the head and neck, most commonly seen in the posterior mandible. Metastasis in the oral region may be the first indication of a distant undiscovered malignancy in up to 60% of patients. Patients with nasopharyngeal cancer report pain that may be referred to the temporomandibular joint region and masquerade as temporomandibular disorder. Orofacial pain has been reported in patients with a distant nonmetastasized cancer, most commonly in the lungs.

The mechanism of pain is thought to be involvement of the vagus or phrenic nerve. Paraneoplastic processes may present with peripheral neuropathies, particularly in patients with lung cancer and lymphoma. Neuropathies are commonly reported in patients with malignancy (1.7%-5.5%) because of the direct effects of the tumor, paraneoplastic syndromes, and treatment-related toxicities.

Orofacial Pain due to Cancer Management

The most common acute oral side effect of radiation therapy and/or cancer chemotherapy is oral mucositis. Oral mucositis and associated pain are the most distressing symptoms reported by patients receiving head and neck radiation therapy and aggressive neutropenia-inducing chemotherapy regimens. Combined chemotherapy and radiation therapy results in increased frequency, severity, and duration of mucositis. (Refer to the Oral Mucositis section of this summary for more information.)

Mucositis pain may interfere with daily activities in approximately one-third of patients, interfering with social activities and mood in more than half. Mucosal pain may persist long after the mucositis resolves. Reports of mucosal sensitivity at 1-year follow-up are common, suggesting that chronic symptoms may be related to tissue change, including epithelial atrophy and/or neuropathy.

Orofacial pain after HNC therapy can be caused by musculoskeletal syndromes, including temporomandibular disorders associated with muscular fibrosis, scar formation, and discontinuity of the jaw. Ablative surgery may lead to tissue defects that may cause significant loss of orofacial function. Resection of the maxilla and mandible leads to sensory impairment, and more than half of patients experience regional hyperalgesia or allodynia. Pain scores after surgery for HNCs are highest for oral cavity cancers, followed by cancers of the larynx and oropharynx.

At more than 6 months postsurgery, impairment due to moderate to severe pain may be seen in approximately one-third of patients. Analgesics and physiotherapy are commonly used in pain management in these patients. Long-term HNC survivors (>3 years) continue to suffer from more pain and functional problems. Surgery-related pain involves inflammatory and neuropathic pain mechanisms.

Postradiation osteonecrosis and bisphosphonate-associated osteonecrosis are recognized oral complications that may cause pain; clinical presentation may include pain, swelling, and bone exposure. Oral GVHD represents a local manifestation of a systemic disease post-HCT that may result in mucosal and arthritic pain. Viral reactivation of herpes viruses may cause pain. Postherpetic neuralgia may result in chronic pain causing painful dysesthesias in the affected area that may persist for years.

Treatment of Pain in Cancer Patients

Pain management should be directed at the diagnoses of etiologic factors, pain mechanisms involved, and pain severity. (Refer to the PDQ summary on Cancer Pain for more information.) Pain mechanisms in cancer include the following:

• Inflammation.
  • Malignant disease.
  • Complications of treatment.
  • Infection.
• Tumor invasion, pressure on structures, or ulceration of mucosal surface.
• Nociceptive pain.
• Neuropathic pain.

Management of pain due to oral mucositis

Oral mucositis pain is associated with release of proinflammatory cytokines and neurotransmitters that activate nociceptors at the site of injury and may be increased by secondary mucosal infection. Pain experience is influenced by anxiety, depression, sociocultural variation, and quality and quantity of sleep.

Topical approaches for mucosal pain relief

Topical anesthetics have a limited duration of effect in mucositis pain (15-30 minutes), may sting with application on damaged mucosa, and affect taste and the gag reflex. Some patients will apply local anesthetics directly to specific sites of ulceration, but no controlled studies have been reported.

Topical anesthetics are often mixed with coating and antimicrobial agents such as milk of magnesia, diphenhydramine, or nystatin but have not been subjected to controlled studies. However, these mixtures result in dilution of each component, which may limit the therapeutic effect. In addition, various agents in the mix may interact, reducing the effect of the components.

Topical benzydamine (not available in the United States), an anti-inflammatory and analgesic/anesthetic agent, has been shown in randomized controlled studies to reduce pain in oral mucositis and reduce the need for systemic analgesics.[2] Other topical approaches include the following:

• A single application of topical doxepin, a tricyclic antidepressant, in cancer patients produces analgesia for 4 hours or longer.[1] Besides producing an extended period of pain relief, application of topical doxepin to damaged mucosa is not accompanied by burning.
• Topical morphine has been shown to be effective for relieving pain,[1] but there is concern about dispensing large volumes of the medication.
• Topical fentanyl prepared as lozenges administered in a randomized placebo-controlled study showed relief of oral mucositis pain.
• Topical capsaicin has been studied for the control of oral mucositis pain [3] but is poorly tolerated by patients. Pretreatment initiation of capsaicin may represent an approach to desensitize patients before the onset of mucositis.

Topical coating agents may reduce pain in mucositis. Coating agents such as sucralfate may have a role to play in mucosal pain management but not in reducing tissue damage.

Systemic medications

Pain management strategies directed at diagnoses and pain mechanisms include the following:

• Topical anesthetics/analgesics.
  • Topical before systemic therapies; if topicals are effective, continue while adding systemic analgesics.
• Systemic analgesics.
• Adjuvant medications (muscle relaxants, anti-inflammatories, antianxiety medications, antidepressants, anticonvulsants).
• Adjuvant therapies (physiotherapy, relaxation, cognitive-behavioral therapies, counseling).
• Palliative radiation therapy.

Additional and nonpharmacologic pain management techniques in oncology include the following:

• Transcutaneous electrical nerve stimulation.
• Cold/moist heat applications.
• Hypnosis.
• Acupuncture.
• Psychological approaches:
  • Distraction.
  • Relaxation/imagery.
  • Cognitive/behavioral therapy.
  • Music therapy, drama therapy.
  • Counseling.

Suggestions for the use of opioids in cancer pain include the following:

• Use the lowest effective dose.
• Base time-contingent prescription on drug characteristics.
• Provide analgesics for breakthrough pain.
• Combine with nonopioid analgesics.
• Provide prophylaxis/treatment for constipation.
• Conduct regular pain assessment and modify management, depending on pain control.
• Follow steps in World Health Organization (WHO) analgesic ladder.

The WHO analgesic ladder is a three-step strategy for managing pain in cancer patients.[4] Pain management must be directed at the severity of pain; the lowest dose of strong opioids (step 3 in the WHO ladder) may be chosen instead of weak opioids for better pain control.[5,6]

Analgesics should be provided on a time-contingent basis to provide a steady state of analgesia; when needed, medication should be available to manage breakthrough pain. Adjuvant medications such as tricyclic antidepressants, gabapentin, and other centrally acting pain medications should be considered, particularly in light of the developing understanding of the common neuropathic mechanisms involved in cancer pain (see list of pain mechanisms).[6,7,8] Regular assessment of pain and modification of pain medications are necessary.

Transdermal fentanyl is widely used for extended duration therapy in the management of pain in the outpatient setting. Cyclooxygenase-2 (COX-2) is upregulated in mucositis; therefore, COX-2 inhibitors represent potential agents that may affect pain and evolution of mucositis.

Adjuvant medications should be used in addition to analgesics. Patients who experienced neuropathic cancer pain and received amitriptyline in addition to morphine were studied in a randomized controlled trial.[9][Level of evidence: I] Limited additional analgesic effect and increased drowsiness, confusion, and dry mouth were observed; however, the central actions of amitriptyline may improve sleep.

Gabapentin is a voltage-sensitive sodium and calcium channel blocker that is used for management of a variety of pain conditions and may improve pain control when used in addition to morphine in cancer patients. Drugs that affect the N-methyl-D-aspartate receptor may affect neuropathic pain; gabapentin is one of these and is well tolerated. Other agents that may be used in pain management include the following:

• Cannabinoids.
• Alpha-2 adrenergic receptor agonists.
• Nicotine.
• Lidocaine.
• Ketamine.

Addiction in opioid therapy is not generally a concern for cancer patients; the focus should be on escalating to stronger opioids as needed (based on assessment) and using adjuvant approaches to provide adequate pain relief. However, the clinician always should be cognizant of potential drug-seeking behavior by the patient.

Tolerance and physical side effects such as constipation, nausea, vomiting, and mental clouding occur with opioids and should be managed prophylactically, if possible. Stool softeners and other approaches to bowel management should be initiated along with the initial opioid prescription. Adequacy of the approach should be assessed regularly.

Nonpharmacologic pain management strategies

In randomized trials, hypnosis has been shown to be a useful pain management strategy for cancer patients. Additional psychological techniques such as counseling, distraction, relaxation techniques, and other cognitive and behavioral training programs have been described (see list of psychological approaches to pain management techniques).

Physical management of orofacial pain includes the use of ice chips for oral cooling, cold compresses, and physical therapy. Acupuncture (refer to the PDQ summary on Acupuncture for more information), transcutaneous nerve stimulation, group therapy, self-hypnosis, relaxation, imagery, cognitive behavioral training, and massage therapy have been considered to alleviate pain in cancer patients. Relaxation and imagery may alleviate pain due to oral mucositis.[1,3];[10][Level of evidence: I][11]

Orofacial Pain Summary

Orofacial pain is common in cancer patients and may be caused by the cancer or its treatment. Orofacial pain is frequently associated with locoregional cancer, but it can also be a sign of systemic and distant cancer.

Pain management requires diagnosis of the various causes and mechanisms of pain in cancer patients. Practitioners must obtain regular pain ratings during the treatment of patients with cancer-related pain. Because pain is frequently multifactorial, addressing each of the dimensions of a patient's pain can improve pain control. Attention should be paid to the patient's overall medical status and oral status.

It is important to recognize and manage the side effects of analgesic therapy, especially those induced by opioids and adjuvant medications. Use of effective topical pain therapy with the initial mucosal injury may allow for reduced duration or reduced doses of systemic medications. Awareness of adjuvant approaches to management is essential; both medications and complementary management with evidence of effect should be considered.

References:

1. Epstein JB, Elad S, Eliav E, et al.: Orofacial pain in cancer: part II--clinical perspectives and management. J Dent Res 86 (6): 506-18, 2007.
2. Kazemian A, Kamian S, Aghili M, et al.: Benzydamine for prophylaxis of radiation-induced oral mucositis in head and neck cancers: a double-blind placebo-controlled randomized clinical trial. Eur J Cancer Care (Engl) 18 (2): 174-8, 2009.
3. Berger A, Henderson M, Nadoolman W, et al.: Oral capsaicin provides temporary relief for oral mucositis pain secondary to chemotherapy/radiation therapy. J Pain Symptom Manage 10 (3): 243-8, 1995.
4. Meuser T, Pietruck C, Radbruch L, et al.: Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93 (3): 247-57, 2001.
5. Eisenberg E, Marinangeli F, Birkhahn J, et al.: Time to modify the WHO analgesic ladder? Pain: Clinical Updates 13 (5): 1-4, 2005. Also available online. Last accessed December 16, 2016.
6. Benedetti C, Brock C, Cleeland C, et al.: NCCN Practice Guidelines for Cancer Pain. Oncology (Williston Park) 14 (11A): 135-50, 2000.
7. Ripamonti C, Dickerson ED: Strategies for the treatment of cancer pain in the new millennium. Drugs 61 (7): 955-77, 2001.
8. Rankin KV, Jones DL, Redding SW, eds.: Oral Health in Cancer Therapy: A Guide for Health Care Professionals. 3rd ed. Austin, Tex: Dental Oncology Education Program, 2008.
9. Mercadante S, Arcuri E, Tirelli W, et al.: Amitriptyline in neuropathic cancer pain in patients on morphine therapy: a randomized placebo-controlled, double-blind crossover study. Tumori 88 (3): 239-42, 2002 May-Jun.
10. Mercadante S, Fulfaro F, Casuccio A: A randomised controlled study on the use of anti-inflammatory drugs in patients with cancer pain on morphine therapy: effects on dose-escalation and a pharmacoeconomic analysis. Eur J Cancer 38 (10): 1358-63, 2002.
11. Epstein JB, Hong C, Logan RM, et al.: A systematic review of orofacial pain in patients receiving cancer therapy. Support Care Cancer 18 (8): 1023-31, 2010.

Infection

The multiple protective-barrier functions associated with normal oral mucosa directly affect risk of acute infection. Normal oral mucosa reduces levels of oral microorganisms colonizing the mucosa by shedding the surface layer; it also limits penetration of many compounds into the epithelium by maintaining a chemical barrier.[1] Normal salivary gland function promotes mucosal health.

Oral mucositis can be complicated by infection in the immunocompromised patient. Specific organisms may play a role in upregulating proinflammatory cytokines via bacterial metabolic products such as liposaccharides. Also, oral organisms can disseminate systemically in the setting of ulcerative oral mucositis and profound, prolonged neutropenia.[2,3,4,5]

Both indigenous oral flora and hospital-acquired pathogens have been associated with bacteremias and systemic infection. As the absolute neutrophil count falls below 1,000/mm³, incidence and severity of infection rise.[6] Patients with prolonged neutropenia are at higher risk of developing serious infectious complications.[7,8] Compromised salivary function can elevate risk of infection of oral origin.

Other oral sites, including the dentition, periapices, and periodontium, can also become acutely infected during myelosuppression secondary to high-dose chemotherapy.[9,10,11,12] A systematic review of the MEDLINE/PubMed and EMBASE databases for articles published between January 1, 1990, and December 31, 2008, reported (from three studies) that the weighted prevalence of dental infection/abscess during chemotherapy was 5.8% (standard of error, 0.009; 95% confidence interval [CI], 1.8-9.7).[13] Dental management before cytoreductive therapy is initiated can substantially reduce the risk of these infectious complications.[14,15,16]

Bacterial Infection

Changes in infection profiles in myelosuppressed cancer patients have occurred over the past three decades. This evolving epidemiology has been caused by multiple factors, including the use of prophylactic and therapeutic antimicrobial regimens and decreased depth and duration of myelosuppression via growth factor therapy.[17] Gram-positive organisms, including viridans streptococci and Enterococci species, are associated with systemic infection of oral origin. In addition, gram-negative pathogens, including Pseudomonas aeruginosa, Neisseria species, and Escherichia coli, remain of concern.

Myeloablated cancer patients with chronic periodontal disease may develop acute periodontal infections, with associated systemic sequelae.[3,9,10,11,12] Extensive ulceration of sulcular epithelium associated with periodontal disease is not directly observable yet may represent a source of disseminated infection by a wide variety of organisms. Inflammatory signs may be masked by the underlying myelosuppression. Thus, neutropenic mouth care protocols that reduce microbial colonization of the dentition and periodontium are important during myelosuppression. Topical therapy may include the following:

• Oral rinses with 0.12% chlorhexidine digluconate.
• Irrigation with effervescent (peroxide) agents, which may affect anaerobic bacteria colonizing the periodontal pocket.
• Gentle mechanical plaque removal, including dental brushing and flossing.

Pulpal/periapical infections of dental origin can cause complications for the chemotherapy patient.[14] Such lesions should be eliminated before chemotherapy begins. Prechemotherapy endodontic therapy should be completed at least 10 days before chemotherapy begins. Teeth with poor prognoses should be extracted, using the 10-day window as a guide. Specific management guidelines are delineated in the NIH Consensus Conference statement.[14,15]

Ill-fitting, removable prosthetic appliances can traumatize oral mucosa and increase the risk of microbial invasion into deeper tissues. Denture-soaking cups can readily become colonized with a variety of pathogens, including P. aeruginosa, E. coli, Enterobacter species, Staphylococcus aureus, Klebsiella species, and Candida albicans. Dentures should be evaluated before chemotherapy begins and adjusted as necessary to reduce risk of trauma. Denture-cleansing solutions should be changed daily. In general, dentures should not be worn when the patient has ulcerative mucositis and is neutropenic (i.e., absolute neutrophil count <500 cells/mm³).

Fungal Infection

Candidiasis

Candidiasis is typically caused by opportunistic overgrowth of C. albicans, a normal inhabitant of the oral cavity in a large proportion of individuals. Several variables contribute to its clinical expression, including drug- or disease-induced immunosuppression, mucosal injury, and salivary compromise. In addition, use of antibiotics may alter the oral flora, thereby creating a favorable environment for fungal overgrowth.[18]

A systematic review indicated that the weighted mean prevalence of clinical oral fungal infection during chemotherapy is 38%.[19] The most common forms of intraoral candidiasis reported in oncology patients are pseudomembranous and erythematous candidiasis.[20,21] Pseudomembranous candidiasis can usually be diagnosed on the basis of its characteristic clinical appearance and may be accompanied by burning pain and taste changes. The appearance of erythematous candidiasis is relatively nonspecific, and laboratory testing may be needed to confirm the diagnosis. It may be accompanied by a burning sensation of the affected tissues.

Topical oral antifungal agents such as nystatin rinse and clotrimazole troches are often used but appear to have variable efficacy in preventing or treating fungal infection in neutropenic patients.[22,23] Patients who wear removable dental prostheses (e.g., partial or full denture) should remove them before the oral antifungal agents are used. Dentures can also be treated by soaking them overnight in the antifungal solution.

Although topical agents may be helpful for superficial oral candidiasis, systemic agents should be used for persistent fungal infections and in patients with significant immunosuppression. Systemic fluconazole is highly effective for prophylaxis and treatment of oral fungal infections in the oncology population.[19]

Noncandidal fungal infections

An increasing number of different fungal organisms are being associated with oral infection in immunocompromised cancer patients, including infection by species of Aspergillus, Mucormycosis, and Rhizopus.[3,23] The clinical presentation is not pathognomonic; lesions may appear similar to lesions caused by other oral toxicities. Microbiologic documentation is essential. Systemic therapy must be instituted promptly because of the high risk of morbidity and mortality.

Viral Infections

Herpes virus

Herpes group viral infections, including those caused by oral lesions, can cause a variety of diseases that range from mild to serious conditions in patients undergoing treatment for cancer.[24] The severity and impact of these lesions and systemic sequelae are directly related to the degree of immunocompromisation of the patient. Comorbid oral conditions such as mucositis or graft-versus-host disease can dramatically increase the severity of oral lesions and significantly increase the difficulty of diagnosis.

In most instances, herpes simplex virus (HSV), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV) infections result from reactivation of latent virus, while cytomegalovirus (CMV) infections can result from either reactivation of a latent virus, or via a newly acquired virus. The viral infections can cause oral mucosal lesions. The prevalence of HSV infection was found to be higher when oral ulcers existed than when no oral ulcers were present.[25]

A systematic review was conducted by the Mucositis Study Group (MSG) of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology.[25] One of the aims of this review was to evaluate studies conducted since 1989 that considered the prevalence of oral viral infections. The reported prevalence of oral HSV infection was 49.8% (95% CI, 31.3-68.2%) among neutropenic cancer patients. The prevalence was much lower in head and neck cancer (HNC) patients who were treated with radiation therapy (0%); however, it rose to 43.2% (95% CI, 0-100%) in irradiated HNC patients who were treated with radiation therapy combined with chemotherapy. This finding is not surprising because neutropenic patients-mainly patients with hematological malignancies-develop deeper immunosuppression during cancer treatment than do other groups of cancer patients. However, the addition of chemotherapy to the conventional radiation therapy increased risks for HNC patients.

With the recognition of the increased risk of HSV and VZV reactivation in seropositive patients who are expected to become profoundly immunosuppressed during cancer therapy, prophylaxis with antiviral medications has drastically reduced the incidence of disease, primarily in patients receiving high-dose chemotherapy and undergoing hematopoietic stem cell transplant (HSCT). The MSG systematic review identified a series of randomized controlled trials testing various antiviral prophylactic protocols.[25] It concluded that there was a significant benefit to using acyclovir to prevent HSV oral infection (at 800 mg/d).[26][Level of evidence: I] In addition, the systematic review pointed out that HSV reactivation was reported in a similar prevalence whether acyclovir or valacyclovir was prescribed [27] and that the prevention of HSV reactivation was achieved in various dosing protocols of valacyclovir (500 or 1,000 mg/d).[27]

The Centers for Disease Control and Prevention (CDC), the Infectious Diseases Society of America (IDSA), and the American Society for Blood and Marrow Transplantation (ASBMT) have published guidelines for the prevention of opportunistic infections in HSCT recipients, which have become a benchmark in this field.[28,29] This significant body of literature presents a global perspective on the prevention of viral infections. CDC, IDSA, and ASBMT concluded that acyclovir prophylaxis is recommended for all HSV seropositive allograft recipients. Valacyclovir instead of acyclovir has been ranked moderately as an effective prevention for HSV in HSCT; foscarnet was mentioned as a drug to avoid for routine HSV prophylaxis because of substantial renal toxicity.

These guidelines extend beyond the MSG systematic review, which failed to provide sufficient evidence (e.g., regarding CMV, VZV, and EBV infections) because the evidence available is not specific for infections with oral involvement. The guidelines of these three U.S. societies are in line with the recommendations of the German Society of Hematology [30] and the European Group for Blood and Marrow Transplantation.[31]

Early diagnosis and prompt therapy remain hallmarks of management. Unfortunately, the available literature [25] and the CDC and ASBMT guidelines [28,29] do not refer to treatment recommendations once a viral infection is diagnosed. As with other infections, risk of systemic dissemination and morbidity/mortality increases with degree and duration of immunocompromisation. The infections can be fatal, depending on degree of immunosuppression.

Herpes simplex virus

Oral herpetic lesions can range from routine herpes labialis to severe stomatitis causing large, painful ulcerations throughout the mouth. The severity of lesions dramatically increases with increasing degrees of immunosuppression. The incidence of recurrent oral HSV lesions in myelosuppressed cancer patients has been considerably reduced with the use of prophylactic acyclovir and valacyclovir regimens.[32,33,34] Additionally, the severity and duration of actual HSV lesions have been reduced by antiviral therapies.

Breakthrough infections are uncommon but can occur. While true resistance to antivirals occurs, clinical infection in the face of antiviral therapy is more likely caused by insufficient dosing or compromised gastrointestinal absorption of oral acyclovir. The introduction of valacyclovir appears to have reduced the incidence of breakthrough oral HSV infections. Topical therapy alone is generally not efficacious in the immunocompromised patient.

In patients who are not receiving antiviral prophylaxis, oral lesions typically emerge concurrent with chemotherapy or chemoradiation therapy during the period of most significant immunosuppression (white blood cell nadir). Typically, in HSCT patients, this represents the period a few days pretransplant through day 35 posttransplant. The risk of HSV reactivation remains higher than normal until immune reconstitution occurs. Similar patterns of risk are noted in patients who are receiving high-dose (immunosuppressive) chemotherapy.

Recurrent oral HSV infections occurring simultaneously with cancer therapy-induced oral mucositis can result in the development of extensive, confluent mucosal ulcerations clinically similar to primary herpetic stomatitis. As such, HSV stomatitis can be confused with cancer therapy-induced ulcerative mucositis. Viral cultures from lesions in HSV seropositive patients are essential for accurate diagnoses. Assays that produce more rapid results, including direct immunofluorescence, shell vial testing, and specific immunoassay for HSV antigen and/or biopsy, may also be useful.

Unlike in myelosuppressed cancer patients, incidence of HSV reactivation in patients undergoing head and neck radiation is very low.[25] Therefore, HSV prophylaxis in patients scheduled to receive head and neck radiation is not recommended.

Varicella-zoster virus

VZV infection classically distributes via dermatomes, although the clinical manifestations can be altered in immunocompromised patients, and multiple dermatomes or more widespread distribution of lesions can be seen. In patients who are receiving high-dose chemotherapy, orofacial VZV lesions are typically observed several weeks after cessation of chemotherapy-unlike HSV, which often occurs within 2 to 3 weeks after chemotherapy is discontinued. For reasons that are not entirely clear, the period of increased risk of VZV reactivation essentially extends from approximately 3 to 12 months posttransplant, with allogeneic transplant recipients being at highest risk. Acyclovir, valacyclovir, and famciclovir are the primary drugs used for treatment.[35]

Cytomegalovirus

Oral lesions associated with CMV have been documented in immunocompromised patients, including those who have undergone marrow transplantation.[3]

Appearance is not pathognomonic and is characterized by multiple mild to moderate ulcerations with irregular margins. The lesions initially present during early periods of marrow regeneration (e.g., 3 weeks after chemotherapy is discontinued) and are characterized by nonspecific pseudomembranous fibrin exudate-covered ulcerations with a granulomatous-appearing base. Surface swab cultures may yield false-negative results, perhaps because of viral propensity for infecting endothelial cells and fibroblasts, with resulting low levels of free virus.

Shell vial cultures can enhance identification of CMV, but CMV-specific immunohistochemical staining of biopsy specimens remains the gold standard. Ganciclovir is the treatment of choice for acute CMV infection. Improved prophylactic measures have reduced the incidence of both primary and recurrent CMV infections.[36][Level of evidence: I][37]

Epstein-Barr virus

EBV is linked to tumor development.[38] In addition, oral hairy leukoplakia has been attributed to EBV infection in immunocompromised patients, as seen in HIV-infected patients and solid organ transplant patients. The lesion does not appear to be clinically significant in chemotherapy recipients, however. In contrast, HSCT patients who are immunocompromised for a prolonged period may be at risk of developing EBV-related lymphomas of the head and neck region, especially when T-cell-depleted grafts are used for allogeneic transplant. As such, risk of EBV infection typically emerges months after cessation of myeloablative therapy used for transplant conditioning.

EBV has been associated with nasopharyngeal carcinomas.[39] After treatment (surgery and/or radiation therapy), anti-EBV antibody titers are often noted to decrease; subsequent increases in titers can be associated with recurrence.

Non-herpes group virus infections

Infections caused by non-herpes viruses are more common in immunocompromised patients, with the risk of infection apparently increasing with the depth and duration of immunosuppression. Oral lesions caused by adenovirus and oral human papilloma virus (HPV) have been described.[3] Often, patients with increased cutaneous HPV lesions will demonstrate oral lesions. These lesions can present as hyperkeratotic verrucoid lesions or as flat acuminata-like lesions.

Restoration of immune function will often result in a digression and, possibly, the disappearance of the oral mucosal lesions. Laser surgery or cryotherapy are typically used to remove oral HPV lesions when medically or cosmetically required; intralesional injections of interferon-alpha may prove effective for recurrent lesions. Infection with Coxsackie viruses can occur but is generally viewed as uncommon. Although adenovirus infections are often implicated as a potential cause of oral lesions, their true incidence is not known.[3]

References:

1. Squier CA, Kremer MJ: Biology of oral mucosa and esophagus. J Natl Cancer Inst Monogr (29): 7-15, 2001.
2. Lalla RV, Brennan MT, Schubert MM: Oral complications of cancer therapy. In: Yagiela JA, Dowd FJ, Johnson BS, et al., eds.: Pharmacology and Therapeutics for Dentistry. 6th ed. St. Louis, Mo: Mosby Elsevier, 2011, pp 782-98.
3. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
4. De Pauw BE, Donnelly JP: Infections in the immunocompromised host: general principles. In: Mandell GL, Bennett JE, Dolin R, eds.: Mandell, Douglas, and Bennett's Principles and Practices of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone, 2000, pp 3079-90.
5. Kennedy HF, Morrison D, Kaufmann ME, et al.: Origins of Staphylococcus epidermidis and Streptococcus oralis causing bacteraemia in a bone marrow transplant patient. J Med Microbiol 49 (4): 367-70, 2000.
6. Rolston KVI, Bodey GP: Infections in patients with cancer. In: Hong WK, Bast RC Jr, Hait WN, et al., eds.: Holland-Frei Cancer Medicine. 8th ed. Shelton, Conn: People's Medical Publishing House-USA, 2010, pp 1921-40.
7. Giamarellou H, Antoniadou A: Infectious complications of febrile leukopenia. Infect Dis Clin North Am 15 (2): 457-82, 2001.
8. Zambelli A, Montagna D, Da Prada GA, et al.: Evaluation of infectious complications and immune recovery following high-dose chemotherapy (HDC) and autologous peripheral blood progenitor cell transplantation (PBPC-T) in 148 breast cancer patients. Anticancer Res 22 (6B): 3701-8, 2002 Nov-Dec.
9. Peterson DE, Minah GE, Overholser CD, et al.: Microbiology of acute periodontal infection in myelosuppressed cancer patients. J Clin Oncol 5 (9): 1461-8, 1987.
10. Graber CJ, de Almeida KN, Atkinson JC, et al.: Dental health and viridans streptococcal bacteremia in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 27 (5): 537-42, 2001.
11. Akintoye SO, Brennan MT, Graber CJ, et al.: A retrospective investigation of advanced periodontal disease as a risk factor for septicemia in hematopoietic stem cell and bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 94 (5): 581-8, 2002.
12. Raber-Durlacher JE, Epstein JB, Raber J, et al.: Periodontal infection in cancer patients treated with high-dose chemotherapy. Support Care Cancer 10 (6): 466-73, 2002.
13. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010.
14. Peterson DE: Pretreatment strategies for infection prevention in chemotherapy patients. NCI Monogr (9): 61-71, 1990.
15. Sonis ST, Woods PD, White BA: Oral complications of cancer therapies. Pretreatment oral assessment. NCI Monogr (9): 29-32, 1990.
16. Peters E, Monopoli M, Woo SB, et al.: Assessment of the need for treatment of postendodontic asymptomatic periapical radiolucencies in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 76 (1): 45-8, 1993.
17. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.
18. Böhme A, Karthaus M, Hoelzer D: Antifungal prophylaxis in neutropenic patients with hematologic malignancies. Antibiot Chemother 50: 69-78, 2000.
19. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010.
20. Nicolatou-Galitis O, Athanassiadou P, Kouloulias V, et al.: Herpes simplex virus-1 (HSV-1) infection in radiation-induced oral mucositis. Support Care Cancer 14 (7): 753-62, 2006.
21. Nicolatou-Galitis O, Velegraki A, Sotiropoulou-Lontou A, et al.: Effect of fluconazole antifungal prophylaxis on oral mucositis in head and neck cancer patients receiving radiotherapy. Support Care Cancer 14 (1): 44-51, 2006.
22. Epstein JB, Vickars L, Spinelli J, et al.: Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 73 (6): 682-9, 1992.
23. Ellis ME, Clink H, Ernst P, et al.: Controlled study of fluconazole in the prevention of fungal infections in neutropenic patients with haematological malignancies and bone marrow transplant recipients. Eur J Clin Microbiol Infect Dis 13 (1): 3-11, 1994.
24. Schubert MM: Oral manifestations of viral infections in immunocompromised patients. Curr Opin Dent 1 (4): 384-97, 1991.
25. Elad S, Zadik Y, Hewson I, et al.: A systematic review of viral infections associated with oral involvement in cancer patients: a spotlight on Herpesviridea. Support Care Cancer 18 (8): 993-1006, 2010.
26. Bergmann OJ, Ellermann-Eriksen S, Mogensen SC, et al.: Acyclovir given as prophylaxis against oral ulcers in acute myeloid leukaemia: randomised, double blind, placebo controlled trial. BMJ 310 (6988): 1169-72, 1995.
27. Warkentin DI, Epstein JB, Campbell LM, et al.: Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients. Ann Pharmacother 36 (10): 1525-31, 2002.
28. Centers for Disease Control and Prevention, Infectious Disease Society of America, American Society of Blood and Marrow Transplantation: Guidelines for preventing opportunistic infections among hematopoietic stem cell transplant recipients. MMWR Recomm Rep 49 (RR-10): 1-125, CE1-7, 2000.
29. Sullivan KM, Dykewicz CA, Longworth DL, et al.: Preventing opportunistic infections after hematopoietic stem cell transplantation: the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation Practice Guidelines and beyond. Hematology Am Soc Hematol Educ Program : 392-421, 2001.
30. Krüger WH, Bohlius J, Cornely OA, et al.: Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the infectious diseases working party (AGIHO) of the german society of haematology and oncology. Ann Oncol 16 (8): 1381-90, 2005.
31. Apperley J, Carreras E, Gluckman E, et al., eds.: The EBMT Handbook: Haematopoietic Stem Cell Transplantation. 6th ed. Paris, France: European School of Haemtology and European Group for Blood and Marrow Transplantation, 2012. Also available online. Last accessed December 16, 2016.
32. Leflore S, Anderson PL, Fletcher CV: A risk-benefit evaluation of aciclovir for the treatment and prophylaxis of herpes simplex virus infections. Drug Saf 23 (2): 131-42, 2000.
33. Reusser P: Management of viral infections in immunocompromised cancer patients. Swiss Med Wkly 132 (27-28): 374-8, 2002.
34. Naesens L, De Clercq E: Recent developments in herpesvirus therapy. Herpes 8 (1): 12-6, 2001.
35. Jubelt B: Valacyclovir and famciclovir therapy in herpes zoster. Curr Neurol Neurosci Rep 2 (6): 477-8, 2002.
36. Burns LJ, Miller W, Kandaswamy C, et al.: Randomized clinical trial of ganciclovir vs acyclovir for prevention of cytomegalovirus antigenemia after allogeneic transplantation. Bone Marrow Transplant 30 (12): 945-51, 2002.
37. Zaia JA: Prevention of cytomegalovirus disease in hematopoietic stem cell transplantation. Clin Infect Dis 35 (8): 999-1004, 2002.
38. Kanegane H, Nomura K, Miyawaki T, et al.: Biological aspects of Epstein-Barr virus (EBV)-infected lymphocytes in chronic active EBV infection and associated malignancies. Crit Rev Oncol Hematol 44 (3): 239-49, 2002.
39. Kumar S, Wairagkar NS, Mahanta J: Demonstration of Epstein-Barr virus antibodies in serum of patients with nasopharyngeal carcinoma. Indian J Cancer 38 (2-4): 72-5, 2001 Jun-Dec.

Hemorrhage

Hemorrhage may occur during treatment-induced thrombocytopenia and/or coagulopathy and is a concern for patients who are receiving high-dose chemotherapy or undergoing hematopoietic stem cell transplantation.[1] Spontaneous gingival oozing may occur when platelet counts drop below 20,000/mm³, especially when there is preexisting gingivitis or periodontitis. Even normal function or routine oral hygiene (brushing and flossing) can induce gingival oozing in the face of preexisting gingivitis and periodontitis.

Although rarely serious, oral bleeds can be of concern to the patient and family. Oral bleeding may be mild (e.g., petechiae located on the lips, soft palate, or floor of the mouth) or severe (e.g., persistent gingival hemorrhage or bleeding from herpes simplex virus ulcers in the face of severe thrombocytopenia).

It is not uncommon for oncology patients to be told specifically to not use toothbrushes and dental floss when their platelet counts drop below 40,000/mm³. This is generally poor advice unless there are extenuating circumstances. Healthy gingival tissues do not bleed unless traumatized. Discontinuation of routine oral hygiene can increase the risk of infection that could not only promote bleeding but also increase the risk of local and systemic infection due to accumulation of bacterial plaque, leading to periodontal infections and tissue breakdown. Such issues further support the utility of pre-cancer therapy dental treatments to reduce or eliminate gingival or periodontal conditions.

The degree of health professional oversight of thrombocytopenic patients is an important consideration relative to risk of mechanical hygiene procedures. With comprehensive monitoring, patients can often safely use dental brushing and flossing throughout the thrombocytopenic episode. Foam brushes are recommended by some practitioners. However, studies have shown that foam brushes cannot adequately remove dental plaque along gingival margins, thus promoting gingival infection and bleeding.

Management of oral bleeds revolves around the use of vasoconstrictors, clot-forming agents, and tissue protectants:

• Epinephrine or cocaine can be used topically to reduce blood flow rates through bleeding vessels.
• Topical thrombin and/or hemostatic collagen agents can be used to organize and stabilize clots.
• Application of mucosal adherent products (including cyanoacrylate products) help seal bleeding sites and protect organized clots.

Patients who tend to form friable and easily dislodged clots will benefit from topical application of aminocaproic acid; in some instances, intravenous administration can be considered to improve coagulation and the formation of stable clots.

Application of 3% hydrogen peroxide and 0.9% saline (1:2 to 1:3 by volume) can aid in wound cleansing and removal of superficial blood debris. Care must be taken not to disturb clots, which might promote bleeding.[1]

References:

1. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.

Neurotoxicity

Selected classes of chemotherapy, including the vinca alkaloids, vincristine, and vinblastine, can cause direct neurotoxicity. Additionally, drugs such as thalidomide and lenalidomide are associated with peripheral neuropathies that can affect the face and jaw. Deep-seated, throbbing mandibular pain can occur. Because this symptom is also consistent with acute dental pulpal disease, it is important that a thorough history and oral physical examination be performed when oral pain is present; radiographs and vitality testing of the dental pulp are typically necessary. After neurotoxicity is appropriately diagnosed, management includes pain support and patient counseling. The symptom generally resolves within a week of discontinuing the causative chemotherapy.

Dental hypersensitivity may occasionally arise in patients weeks or months after they discontinue chemotherapy. Additionally, it has been observed that patients being treated with cyclosporine for treatment of graft-versus-host disease will report increased thermal sensitivity. The mechanisms of this response are not known. Fortunately, thermal stimuli are self-resolving after discontinuation or withdrawal of therapy, though they can persist for several months. Topical application of fluorides and/or desensitizing toothpaste may ameliorate the discomfort.

Patients may experience temporomandibular dysfunction pain involving muscles of mastication, temporomandibular joints, or teeth. This condition is not unique to cancer patients, and it correlates with stress and dysfunctional habits including bruxism and clenching of the jaws. Stress and sleep dysfunction appear to be the most frequent etiologic factors. Judicious use of muscle relaxants or anxiety-reducing agents plus physical therapy (moist heat applications, massage, and gentle stretching) are standard approaches for management. For patients with a propensity for clenching or bruxism during sleep, customized occlusal splints for use while sleeping may be of value.

Graft-versus-Host Disease

Patients who have received allogeneic or matched unrelated transplants are at risk of developing graft-versus-host disease (GVHD).[1,2] A related condition referred to as pseudo-GVHD is occasionally reported in autologous hematopoietic stem cell transplant recipients. GVHD can affect oral tissues and often mimics naturally occurring autoimmune diseases such as erosive lichen planus, pemphigus, scleroderma, and Sjögren syndrome. Oral GVHD has also been linked to oral precancerous and malignant lesions.[3]

Acute GVHD can occur as early as 2 to 3 weeks posttransplant; mucosal erythema and erosion/ulceration are typical manifestations. Chronic oral GVHD changes can be recognized as early as day 70 posttransplant.[4] The pattern and types of lesions seen in acute GVHD are also seen in chronic GVHD, but manifestations can also include raised white hyperkeratotic plaques and striae and persistent reduced salivary function. Oral symptoms of oral GVHD include xerostomia and increased sensitivity and pain with spices, alcohols, and flavoring agents (especially mint flavors in toothpaste and oral care products). Patients may also suffer from odynophagia and dysphagia due to gastrointestinal involvement.[5] All of these symptoms of GVHD may lead to weight loss and malnutrition.[6]

Biopsy of oral mucosa, including both surface epithelium and minor labial salivary glands, may be of value in establishing a final diagnosis.[7,8] Presence of a lymphocytic infiltrate (grade I) with epithelial cell necrosis (grade II) provides the diagnostic basis for oral GVHD. As clinical criteria for recognition of oral signs and symptoms of GVHD have become more established, dependance on the oral biopsy to diagnose oral involvement has lessened. In cases of equivocal examination findings, the biopsy can improve the recognition of oral involvement.

Topical management of mucosal lesions may include steroids, azathioprine, and/or oral psoralen and ultraviolet A (PUVA) therapy (refer to the list on Management of Oral GVHD).[4,9] While topical cyclosporin has been suggested as therapeutically beneficial, its effectiveness is less predictable than that of other treatments-which, when coupled with increased cost of care, usually decreases its utility. The use of FK506 and mycophenolate mofetil to topically treat oral GVHD remains anecdotal and of uncertain efficacy. Systemic therapy (e.g., prednisone, budesonide, cyclosporine, mycophenolate mofetil, and other immunosuppressive agents) is routinely necessary, primarily to treat the condition. Topical treatment can be used to specifically manage oral sensitivity and help heal ulcerations. Patients with clinically significant xerostomia may benefit from pilocarpine (5 mg 3 or 4 times a day) or cevimeline (10 mg 4 times a day) if native salivary gland function remains partially intact.

Submucosal and/or dermal fibrosis can occur in persistent cases of chronic GVHD. This scleroderma-like complication can be subtle and appear as slight mucosal or skin tightness, or it can progress to skin thickening and fibrosis. Intraoral submucosal fibrotic bands have been noted to significantly restrict the oral opening. Successful management of GVHD with systemic therapy will usually see resolution and/or significant resolution of this problem. However, in rare instances, surgical or chemical techniques to disrupt fibrotic bands can be required to improve the oral opening.

Management of Oral GVHD

• Topical steroids:
  • Rinses: dexamethasone elixir (Decadron 0.1 mg/mL).
  • Gels, creams:
    • fluocinonide (Fluonex)
    • clobetasol (Temovate)
    • halobetasol (Ultravate)
    • betamethasone (Celestone)
  • Powders: beclomethasone (Beclovent) (inhalers applied to mucosa).
• Other topical immunosuppressants:
  • azathioprine rinse (Imuran; 5-10 mg/mL)
  • cyclosporin (Neoral)
• Antifungals (when concomitant oral fungal infection is documented):
  • Topical preparations:
    • nystatin (Mycostatin)
    • clotrimazole (Mycelex)
    • amphotericin solution (Amphocin; in the United States, this is compounded)
  • Systemic agents:
    • fluconazole (Diflucan)
    • itraconazole (Sporanox)
• PUVA.
• Sialogogues:
  • cevimeline (Evoxac)
  • pilocarpine (Salagen)
  • bethanechol
• Topical anesthetics:
  • lidocaine (Xylocaine)
  • dyclonine (Dyclone)
  • diphenhydramine (Benadryl)
  • doxepin (Zonalon)
• Dental caries prevention:
  • Oral hygiene (dental plaque removal)
  • Fluorides:
    • Adult patients: brush-on products, rinses, home-use trays
    • Pediatric patients: brush-on gel (if patient can dependably expectorate the fluoride gel after application)

    If drinking water does not contain enough fluoride to prevent tooth decay, oral fluoride (e.g., drops or vitamins) should be provided to children younger than 12 years.

  • Remineralizing solution (calcium phosphate ± fluoride preparations)

References:

1. Schubert MM, Sullivan KM: Recognition, incidence, and management of oral graft-versus-host disease. NCI Monogr (9): 135-43, 1990.
2. Demarosi F, Bez C, Sardella A, et al.: Oral involvement in chronic graft-vs-host disease following allogenic bone marrow transplantation. Arch Dermatol 138 (6): 842-3, 2002.
3. Abdelsayed RA, Sumner T, Allen CM, et al.: Oral precancerous and malignant lesions associated with graft-versus-host disease: report of 2 cases. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 93 (1): 75-80, 2002.
4. Schubert MM, Peterson DE: Oral complications of hematopoietic cell transplantation. In: Appelbaum FR, Forman SJ, Negrin RS, et al., eds.: Thomas' Hematopoietic Cell Transplantation: Stem Cell Transplantation. 4th ed. Oxford, UK: Wiley-Blackwell, 2009, pp 1589-1607.
5. Schima W, Pokieser P, Forstinger C, et al.: Videofluoroscopy of the pharynx and esophagus in chronic graft-versus-host disease. Abdom Imaging 19 (3): 191-4, 1994 May-Jun.
6. Jacobsohn DA, Margolis J, Doherty J, et al.: Weight loss and malnutrition in patients with chronic graft-versus-host disease. Bone Marrow Transplant 29 (3): 231-6, 2002.
7. Loughran TP Jr, Sullivan K, Morton T, et al.: Value of day 100 screening studies for predicting the development of chronic graft-versus-host disease after allogeneic bone marrow transplantation. Blood 76 (1): 228-34, 1990.
8. Yamada H, Chihara J, Hamada K, et al.: Immunohistology of skin and oral biopsies in graft-versus-host disease after bone marrow transplantation and cytokine therapy. J Allergy Clin Immunol 100 (6 Pt 2): S73-6, 1997.
9. Epstein JB, Nantel S, Sheoltch SM: Topical azathioprine in the combined treatment of chronic oral graft-versus-host disease. Bone Marrow Transplant 25 (6): 683-7, 2000.

Posttransplantation Dental Treatment

Caution should be exercised when considering dental treatment for transplant patients until immune reconstitution has occurred; the time frame for this reconstitution can vary from 6 months to 12 months. Although hematologic parameters, including complete blood count and differential, may be documented as within normal limits, functional immune abnormalities may still be present. Patients should not resume routine dental treatment, including dental scaling and polishing, until adequate immunologic reconstitution has occurred; this includes recovery from graft-versus-host disease. The aerosolization of debris and bacteria during the use of ultrasonic or high-speed rotary cutting instruments can put the patient at risk for aspiration pneumonia; additionally, bacteremias often occur as a result of dental treatment, and their impact can be noticeable.

For patients who need urgent or emergency dental treatment, prophylactic antibiotics and strategies to reduce the potential influence of aspirating dental aerosols should be used. Additional administration of antibiotics should be determined by the patient's risk of infection caused by the presenting condition or as a sequela of treatment.

Appropriate supportive care-including antibiotics, immunoglobulin G administration, adjustment of steroid doses, and/or platelet transfusions-should be comprehensively considered before invasive oral procedures are undertaken.

Relapse and Second Malignancy

Gingival infiltrates, oral infection, and/or bleeding disproportionate to local etiology can indicate possible relapsed disease, especially in patients treated for leukemias or lymphomas. Additionally, localized oral plasmacytomas have been observed in patients relapsing early post-autologous transplantation for multiple myeloma. Painless unilateral lymphadenopathy can also represent relapse in patients with previously treated lymphoma. Lymphoproliferative diseases occurring as second primary malignancies posttransplant must be considered for soft tissue masses and lymphadenopathy noted in transplant recipients.

Incidence of second malignancy steadily increases as cancer patients survive longer posttransplant. Previous exposure to chemotherapy and radiation therapy and alterations in immune function, graft-versus-host disease (GVHD), and GVHD therapy collectively contribute to risk of second malignancy. Oral squamous cell carcinoma is the most frequently occurring secondary oral malignancy in transplant patients, with the lips and tongue being the most frequently reported sites.

Dysgeusia

In stem cell transplant patients, dysgeusia can occur secondary to either chemotherapy/chemoradiation conditioning or graft-versus-host disease. Refer to the Dysgeusia section in the Conditions Affected By Both Chemotherapy and Head/Neck Radiation section of this summary for management recommendations.

Oral Toxicities Not Related to Chemotherapy or Radiation Therapy

Osteonecrosis of the Jaw Associated With Medications (ONJ)

The first reported cases of osteonecrosis of the jaw associated with medications (ONJ) were seen in patients taking bisphosphonates.[1,2,3] Bisphosphonates are potent inhibitors of osteoclasts. They are used in cancer patients with skeletal metastasis, including breast, prostate, or lung cancer; and in patients with multiple myeloma. Bisphosphonates are also used to treat hypercalcemia of malignancy. Bisphosphonates reduce the risk of fracture and skeletal pain, improving the quality of life of patients with malignant bone disease.[4] (Refer to the PDQ summary on Cancer Pain for more information.)

Evidence in the medical and dental literature reveals several cases of ONJ reported with the use of drugs other than bisphosphonates, including the following:[5,6]

• Denosumab, a human monoclonal antibody that inhibits the receptor activator of nuclear factor kappa beta ligand (RANKL).
• The antiangiogenic drugs being tested in advanced cancer cases, including bevacizumab, sunitinib, and possibly sorafenib.

With the approval of a new antiresorptive medication, denosumab, a fully humanized monoclonal antibody that targets RANKL and that has indications similar to those of the bisphosphonates, additional reports confirmed that this new drug can also cause ONJ. Subsequently, the introduction of antiangiogenic medications in clinical trials in oncology revealed that these agents can also be associated with ONJ development, either as single drugs or when used in combination with antiresorptives. When antiangiogenics are used in combination with bisphosphonates, the risk of ONJ increases significantly.[7]

Thus, osteonecrosis of the jaw is no longer a problem exclusively associated with the use of bisphosphonates; it is also associated with the use of other drugs such as the monoclonal antibody denosumab and antiangiogenics such as bevacizumab and sorafenib. For this reason, it is proposed that the nomenclature that refers to this pathology be changed to ONJ, meaning osteonecrosis of the jaw that is associated with medications.

ONJ is an oral complication of antiresorptive therapy in cancer patients.[8] First reported in 2003,[1,2,3] ONJ is defined as the unexpected appearance of exposed necrotic bone anywhere in the oral cavity of an individual who is receiving drugs that have been associated with ONJ (bisphosphonates, denosumab, and antiangiogenics) and who has not received radiation therapy to the head and neck. The exposed bone persists for at least 6 to 8 weeks, despite the provision of standard dental care. It is also possible that symptoms of dental disease, periodontal disease, or both may be present, without visible exposed bone.[9] The occurrence of ONJ is based on cases reported in the literature, and occurrence ranges from between 1% and 10% for patients receiving the intravenous formulation (pamidronate and zoledronic acid) to less than 1% for patients taking oral bisphosphonates.[10,11]

A study evaluating the literature until December 2008 found that the prevalence of ONJ can vary according to study design and the type of bisphosphonate used. For example, studies in which patient evaluation and follow-up are conducted by dental professionals have an overall prevalence of 7.3%, whereas survey studies of large populations of patients have a prevalence of less than 1%. If the prevalence is calculated on the basis of type of bisphosphonate used, then the prevalence of cases of ONJ in which a combination of zoledronic acid and pamidronate is used over the course of therapy can be as high as 24.5%.[12] The mandible is affected in approximately 68% of cases, the maxilla in about 28% of cases, and both jawbones in approximately 4% of cases.[13] However, there have been reports of evidence of ONJ in other parts of the head and neck and skeleton.[14,15,16]

ONJ incidence, risk factors, and outcomes were assessed in an analysis of three phase III trials in patients who had metastatic bone disease secondary to solid tumors or myeloma and who were receiving antiresorptive therapies.[17] Patients were assigned to receive either subcutaneous injections of denosumab (120 mg) or intravenous administration of zoledronic acid (4 mg) every 4 weeks. Oral examinations were performed at baseline and every 6 months. Oral adverse events were adjudicated by a panel of dental experts. Of 5,723 patients enrolled, 89 (1.6%) were diagnosed with ONJ; 37 received zoledronic acid, and 52 received denosumab. Tooth extraction was reported for two-thirds of patients with ONJ. As of October 2010, ONJ resolved in 36% of patients (29.7% for zoledronic acid and 40.4% for denosumab). A combined analysis of these trials found that ONJ was an infrequent event, management was mostly conservative, and healing occurred in more than one-third of the patients. Bone-targeted therapy may help reduce the rate of ONJ and improve outcomes.[17]

When denosumab was compared to placebo in a study of men with nonmetastatic, high-risk, castration-resistant prostate cancer in which patients received treatment for at least 24 months, ONJ incidence was 4.6% in patients treated with denosumab; there were no cases of ONJ in the placebo group.[18] Therefore, time on medication can be a factor in the development of ONJ.

Risk factors for ONJ include the following:

• Dental extractions.[19][Level of evidence: II][20]
• Ill-fitting dentures.[19]
• Intravenous bisphosphonate (zoledronic acid, denosumab).[19,20][Level of evidence: I][12];[21][Level of evidence: I]
• Time on medication.[12,18,20]
• Multiple myeloma.[12]

The incidence of ONJ may be reduced by the implementation of dental preventive measures before bisphosphonate therapy is initiated in solid-tumor patients with bone metastases.[22,23]

Diagnosis of ONJ

Diagnosis of ONJ can be clinically challenging. The most common clinical presentations are as follows:

• Classical: a cancer patient with skeletal metastasis who is receiving intravenous bisphosphonate or denosumab therapy and who presents with visible necrotic bone in the oral cavity. The site may be infected and painful; these conditions are the typical reason for referral to a dentist. Pain results both from inflammation of the soft tissues contiguous to the necrotic bone and from infection. Other symptoms typically occur in more advanced cases (e.g., paresthesia secondary to local neurologic involvement). Purulent secretion at the exposed area indicates active infection. Radiographic examination may demonstrate typical radiolucent and radiopaque areas associated with a bone sequestrum. Bone trabeculation may present with a moth-eaten appearance, suggesting ongoing bone destruction. Lesions can arise secondary to surgical dental treatments (e.g., dental extractions or periodontal surgery), significant dental infections, or trauma. Alternatively, ONJ can arise spontaneously, without any detectable trauma or predisposing treatment.
• Less common: a cancer patient receiving intravenous bisphosphonate or denosumab therapy who complains of pain that mimics periodontal or pulpal pathology. There is no clinically visible exposed necrotic bone, but a draining fistula or purulent secretion from the periodontal sulcus may exist. The involved teeth will typically be symptomatic upon palpation and percussion.
• Occasional: a cancer patient who complains of oral pain and discomfort, but a definitive diagnosis of ONJ cannot be made because no clinically exposed bone is evident. In these patients, the most likely clinical diagnosis should be addressed first. It is important to recognize that antiresorptive administration can result in bone pain, including to areas of the head and neck and jaws; this possible etiology for jaw symptoms should be considered as additional dental diagnoses are pursued. Routine clinical pulp testing and assessing for signs and symptoms of periodontal disease (e.g., pocket depths, bone loss, and bleeding on probing) should be performed. Radiographic examination should also be conducted. Although not yet definitively confirmed in the literature, the radiographic finding of sclerosing or absence of the lamina dura of the involved teeth may indicate the early presence of ONJ.[13][Level of evidence: III]

  Endodontic and periodontal therapy should be performed first. The patient should be advised about the possibility of ONJ and should be educated about oral hygiene procedures. If dental extraction is indicated, the possibility of subclinical ONJ should be considered and explained to the patient. Thus, delay or absence of healing postextraction must be considered as risk for ultimate development of ONJ. Before the invasive procedure is performed, the risk of excessive bleeding and/or infection due to bone marrow suppression must be discussed with the patient's physician, and proper preventive measures should be formulated.

Management of ONJ

Confirmed ONJ with exposed bone in the oral cavity should initially be managed conservatively with local debridement and removal of sharp margins of bone; this reduces the risk of trauma to soft tissue, including the tongue. Systemic antibiotics should be administered when active infection with purulent secretion, swelling and inflammation of the surrounding soft tissues, and pain are present. Initial therapy can be implemented with a single antibiotic, but there is no agreement regarding drug of first choice. Options include the following:

• Amoxicillin, 500 mg 4 times a day for at least 14 days.
• Metronidazole, 250 mg 3 times a day for at least 14 days.
• Clindamycin, 300 mg 4 times a day for at least 14 days.
• Amoxicillin and clavulanic acid, 500 mg 4 times a day for at least 14 days.

In addition, topical oral therapy can be implemented via 0.12% chlorhexidine mouth rinses or tetracycline rinses (62.5 mg/oz) twice a day. The need for oral hygiene with meticulous brushing and flossing after meals should be emphasized.[4,10,11,13,24,25]

The patient should be reevaluated in 2 weeks. Systemic antibiotics can be discontinued when clinical signs and symptoms improve. The local measures should be maintained, however, as part of the routine oral hygiene procedures consisting of brushing and flossing.

In ONJ cases refractory to therapy, patients may need to be maintained on long-term antibiotic therapy. With these patients, a combination of different antibiotic agents such as penicillin and metronidazole can be considered. Another possibility is to use clindamycin or the combination of amoxicillin and clavulanic acid in place of amoxicillin. When the infectious process extends to more critical areas of the head and neck, the patient may need hospitalization and intravenous antibiotic therapy, culminating in the need for extensive surgical resection of the affected areas.[25]

Reports suggest that ONJ can be successfully managed by surgical resection and primary wound closure, especially in cases refractory to conservative therapy.[26,27,28] The use of radical surgery is increasing, and it appears that the initial paradigm that surgery should not be done in ONJ cases is no longer true. However, patients must be advised that surgery may result in treatment failure and that not all cases are treated successfully. With surgery as a treatment option, clinicians are now performing bone biopsies to confirm ONJ diagnoses. In cancer patients, there is always a possibility of metastatic disease to the jawbones mimicking ONJ; the final diagnosis should be confirmed by histopathological examination.[29] The use of surgical lasers has also been suggested as an alternative for ONJ patients who do not respond to conservative management.[30]

The use of hyperbaric oxygen therapy (HBO) to treat cases of established ONJ does not appear to be effective.[4,13,24,25] However, evidence indicates that HBO in addition to discontinuation of bisphosphonate therapy may benefit patients with ONJ.[31] Definitive evidence is pending while research in this area continues.[32]

Another possible approach involves surgical manipulation and uses bone labeling with tetracycline. In this modality, the patient is treated with a standard dose of tetracycline a few days presurgery. During the surgery, when bone is exposed, the Wood's lamp is shone over the bone. Necrotic bone does not fluoresce and is removed. The procedure continues until fluorescence is seen, suggesting the presence of vital bone.[33]

The American Association of Oral and Maxillofacial Surgeons proposed a staging system for ONJ and suggested treatment strategies (see Table 6, adapted from the guidelines paper [34]).

Discontinuation of bisphosphonate therapy

The literature does not support discontinuing bisphosphonate therapy to enhance the healing process. Bisphosphonates accumulate in a patient's skeleton and could remain active for several years, especially in patients who have been treated with an intravenous bisphosphonate for longer than a year. There is anecdotal evidence that even with discontinuing zoledronic acid therapy for patients who develop ONJ, the osteonecrotic process clinically progresses and can extend to contiguous sites. However, discontinuing bisphosphonate therapy is advocated by some authors, especially when a procedure to treat ONJ is planned.[10,13]

Some clinicians believe that discontinuing the drug for patients scheduled for surgery to treat the necrotic area may be beneficial, although this belief is not supported by scientific study. It is recommended that such a drug holiday be maintained until clinical evidence of healing is observed.[10] However, controversy surrounds this issue,[11][Level of evidence: IV] and further research is needed.

In summary, a potential drug holiday for patients on bisphosphonates must be considered in the context of presence or absence of osteonecrosis. In view of the lack of scientific evidence from randomized controlled studies, risk and benefits of drug discontinuation must be determined by the prescribing physician. In patients who are being treated with bisphosphonate therapy and who need invasive procedures, there is no scientific information that supports a drug holiday and that this will prevent the development of ONJ. In patients with osteonecrosis who need invasive procedures, a drug holiday may be beneficial.[35] On the other hand, there is emerging evidence that patients with multiple myeloma and osteonecrosis may be maintained on bisphosphonate therapy without the risk of progression of the osteonecrotic process.[36]

It is advisable to discuss with the patient's physician whether discontinuing bisphosphonate therapy will not put the patient's general health at risk. Obtaining an informed consent from the patient before execution of the proposed drug discontinuation and therapy is important.

Spontaneous and asymptomatic ONJ

Patients may present with asymptomatic exposed necrotic bone anywhere in the oral cavity, although the mylohyoid plate on the posterior mandible and the mandibular tori are the most frequently affected sites. In this case, local measures and effective oral hygiene are important, as is systematic reevaluation of the patient to ensure resolution.

Effects on quality of life

The number of patients who develop ONJ is small compared with the large number of people who take bisphosphonates. However, some lesions can progress to large sizes and cause severe changes in a patient's quality of life.[4,8] Advanced mandibular lesions, for instance, can cause necrosis of the cortical bone, increasing the risk of fractures.[4] Advanced and nonresponsive infections may require hospitalization and intravenous antibiotic therapy.[4] Advanced cases of ONJ may require extensive jawbone resection.[37] Therefore, this adverse effect of bisphosphonate therapy may negatively affect quality of life.

Tobacco use and ONJ

The discontinuation of tobacco use to favor the healing process has been recommended.[38] However, the role of tobacco and other comorbidities in the process of ONJ formation is still under investigation.[13]

References:

1. Ruggiero SL, Mehrotra B, Rosenberg TJ, et al.: Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62 (5): 527-34, 2004.
2. Marx RE: Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic. J Oral Maxillofac Surg 61 (9): 1115-7, 2003.
3. Migliorati CA: Bisphosphanates and oral cavity avascular bone necrosis. J Clin Oncol 21 (22): 4253-4, 2003.
4. Migliorati CA, Casiglia J, Epstein J, et al.: Managing the care of patients with bisphosphonate-associated osteonecrosis: an American Academy of Oral Medicine position paper. J Am Dent Assoc 136 (12): 1658-68, 2005.
5. Migliorati CA, Covington JS 3rd: New oncology drugs and osteonecrosis of the jaw (ONJ). J Tenn Dent Assoc 89 (4): 36-8; quiz 38-9, 2009.
6. Yarom N, Elad S, Madrid C, et al.: Osteonecrosis of the jaws induced by drugs other than bisphosphonates - a call to update terminology in light of new data. Oral Oncol 46 (1): e1, 2010.
7. Smidt-Hansen T, Folkmar TB, Fode K, et al.: Combination of zoledronic Acid and targeted therapy is active but may induce osteonecrosis of the jaw in patients with metastatic renal cell carcinoma. J Oral Maxillofac Surg 71 (9): 1532-40, 2013.
8. Migliorati CA, Siegel MA, Elting LS: Bisphosphonate-associated osteonecrosis: a long-term complication of bisphosphonate treatment. Lancet Oncol 7 (6): 508-14, 2006.
9. Ruggiero SL, Dodson TB, Fantasia J, et al.: Medication-Related Osteonecrosis of the Jaw-2014 Update. Rosemont, Ill: American Association of Oral and Maxillofacial Surgeons, 2014. Available online. Last accessed December 16, 2016.
10. Woo SB, Hellstein JW, Kalmar JR: Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144 (10): 753-61, 2006.
11. Khosla S, Burr D, Cauley J, et al.: Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 22 (10): 1479-91, 2007.
12. Migliorati CA, Woo SB, Hewson I, et al.: A systematic review of bisphosphonate osteonecrosis (BON) in cancer. Support Care Cancer 18 (8): 1099-106, 2010.
13. Marx RE, Sawatari Y, Fortin M, et al.: Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment. J Oral Maxillofac Surg 63 (11): 1567-75, 2005.
14. Polizzotto MN, Cousins V, Schwarer AP: Bisphosphonate-associated osteonecrosis of the auditory canal. Br J Haematol 132 (1): 114, 2006.
15. Khan AM, Sindwani R: Bisphosphonate-related osteonecrosis of the skull base. Laryngoscope 119 (3): 449-52, 2009.
16. Longo R, Castellana MA, Gasparini G: Bisphosphonate-related osteonecrosis of the jaw and left thumb. J Clin Oncol 27 (35): e242-3, 2009.
17. Saad F, Brown JE, Van Poznak C, et al.: Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23 (5): 1341-7, 2012.
18. Smith MR, Saad F, Coleman R, et al.: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet 379 (9810): 39-46, 2012.
19. Vahtsevanos K, Kyrgidis A, Verrou E, et al.: Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol 27 (32): 5356-62, 2009.
20. Hoff AO, Toth BB, Altundag K, et al.: Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23 (6): 826-36, 2008.
21. Stopeck AT, Lipton A, Body JJ, et al.: Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28 (35): 5132-9, 2010.
22. Ripamonti CI, Maniezzo M, Campa T, et al.: Decreased occurrence of osteonecrosis of the jaw after implementation of dental preventive measures in solid tumour patients with bone metastases treated with bisphosphonates. The experience of the National Cancer Institute of Milan. Ann Oncol 20 (1): 137-45, 2009.
23. Fusco V, Galassi C, Berruti A, et al.: Decreasing frequency of osteonecrosis of the jaw in cancer and myeloma patients treated with bisphosphonates: the experience of the oncology network of piedmont and aosta valley (north-Western Italy). ISRN Oncol 2013: 672027, 2013.
24. Migliorati CA, Schubert MM, Peterson DE, et al.: Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone: an emerging oral complication of supportive cancer therapy. Cancer 104 (1): 83-93, 2005.
25. Ruggiero SL, Fantasia J, Carlson E: Bisphosphonate-related osteonecrosis of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 102 (4): 433-41, 2006.
26. Carlson ER, Basile JD: The role of surgical resection in the management of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 85-95, 2009.
27. Stockmann P, Vairaktaris E, Wehrhan F, et al.: Osteotomy and primary wound closure in bisphosphonate-associated osteonecrosis of the jaw: a prospective clinical study with 12 months follow-up. Support Care Cancer 18 (4): 449-60, 2010.
28. Williamson RA: Surgical management of bisphosphonate induced osteonecrosis of the jaws. Int J Oral Maxillofac Surg 39 (3): 251-5, 2010.
29. Gander T, Obwegeser JA, Zemann W, et al.: Malignancy mimicking bisphosphonate-associated osteonecrosis of the jaw: a case series and literature review. Oral Surg Oral Med Oral Pathol Oral Radiol 117 (1): 32-6, 2014.
30. Vescovi P, Manfredi M, Merigo E, et al.: Surgical approach with Er:YAG laser on osteonecrosis of the jaws (ONJ) in patients under bisphosphonate therapy (BPT). Lasers Med Sci 25 (1): 101-13, 2010.
31. Freiberger JJ, Padilla-Burgos R, Chhoeu AH, et al.: Hyperbaric oxygen treatment and bisphosphonate-induced osteonecrosis of the jaw: a case series. J Oral Maxillofac Surg 65 (7): 1321-7, 2007.
32. Freiberger JJ: Utility of hyperbaric oxygen in treatment of bisphosphonate-related osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (5 Suppl): 96-106, 2009.
33. Pautke C, Bauer F, Tischer T, et al.: Fluorescence-guided bone resection in bisphosphonate-associated osteonecrosis of the jaws. J Oral Maxillofac Surg 67 (3): 471-6, 2009.
34. Ruggiero SL, Dodson TB, Assael LA, et al.: American Association of Oral and Maxillofacial Surgeons position paper on bisphosphonate-related osteonecrosis of the jaw - 2009 update. Aust Endod J 35 (3): 119-30, 2009.
35. Dickinson M, Prince HM, Kirsa S, et al.: Osteonecrosis of the jaw complicating bisphosphonate treatment for bone disease in multiple myeloma: an overview with recommendations for prevention and treatment. Intern Med J 39 (5): 304-16, 2009.
36. Berenson JR, Yellin O, Crowley J, et al.: Prognostic factors and jaw and renal complications among multiple myeloma patients treated with zoledronic acid. Am J Hematol 86 (1): 25-30, 2011.
37. Chaudhry AN, Ruggiero SL: Osteonecrosis and bisphosphonates in oral and maxillofacial surgery. Oral Maxillofac Surg Clin North Am 19 (2): 199-206, vi, 2007.
38. Yarom N, Yahalom R, Shoshani Y, et al.: Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome. Osteoporos Int 18 (10): 1363-70, 2007.

Head / Neck Radiation Patients

Head and neck radiation patients are a significant challenge relative to both intratherapy and posttherapy oral complications resulting from radiation therapy. Unlike the oral complications of chemotherapy that are of shorter duration and significant for only a short period (a few weeks to 2 months) after the cessation of therapy, the oral complications of head and neck radiation are more predictable, are often more severe, and can lead to permanent tissue changes that put the patient at risk for serious chronic complications.

Preradiation Dental Evaluation and Oral Disease Stabilization

Elimination of oral disease and implementation of oral care protocols designed to maintain maximum oral health must be components of patient assessment and care before radiation therapy begins. During and after radiation therapy, oral management will be dictated by the following:

• Specific needs of the patient.
• Specifics of the radiation therapy.
• Chronic complications caused by radiation therapy.

Ongoing oral assessment and treatment of complications are essential because radiation to oral tissues typically conveys a lifelong risk of oral complications. In addition, invasive oral procedures can cause additional sequelae. Dental care typically needs to be altered because of underlying chronic radiation-induced tissue damage.

Patients should receive a comprehensive oral evaluation several weeks before high-dose upper-mantle radiation begins. This timing provides an appropriate interval for tissue healing in the event that invasive oral procedures, including dental extractions, dental scaling/polishing, and endodontic therapy, are necessary. The goal of this evaluation is to identify teeth at significant risk of infection and/or breakdown that would ultimately require aggressive or invasive dental treatment during or after the radiation that increases the risk of soft tissue necroses and osteonecroses. The likelihood of these lesions occurring postradiation increases over the patient's lifetime as the risk of significant dental disease (restorative, periodontal, and endodontic) increases. Salivary gland hypofunction and xerostomia frequently occur postradiation. It is thus especially important that preradiation dental care strategies are instituted to reduce the impact of the complications of severely decreased saliva secretion and the associated high risk of dental caries.

In addition, three radiation-specific issues emerge:

1. Radiation injury is oral tissue-specific and dependent on dosage and portals of therapy.
2. Radiation-induced oral mucositis typically lasts 6 to 8 weeks, versus the approximate 5 to 14 days observed in chemotherapy patients. The extended radiation treatment protocols are chiefly responsible for this difference.
3. The primary cause of oral cancer is tobacco use; alcohol abuse further escalates risk. It is therefore critical that head/neck cancer patients permanently cease tobacco use.
   • Most patients with smoking-related cancer appear motivated to quit smoking at the time of cancer diagnosis.
   • Continued smoking substantially increases the likelihood of recurrence or occurrence of a second cancer in survivors, particularly in those who previously received radiation therapy.
   • A stepped-care approach to tobacco cessation is recommended, including direct physician advice to quit and provision of basic information to all patients at each contact during the first month of diagnosis, followed by more intensive pharmacologic treatment or counseling for those having difficulty quitting or remaining abstinent.

Oral Complications of Head and Neck Radiation

The oral complications of head and neck radiation can be divided into two groups on the basis of the usual time of their occurrence:

• Acute complications occurring during therapy.
• Late complications occurring after radiation therapy has ended.

Acute complications include the following:

• Oropharyngeal mucositis.[1]
• Sialadenitis and xerostomia.
• Infections (primarily candidiasis).
• Taste dysfunction.

Occasionally, tissue necrosis can be seen late during therapy, but this is relatively rare.

Chronic complications include the following:

• Mucosal fibrosis and atrophy.
• Decreased saliva secretion and xerostomia.[1]
• Accelerated dental caries related to compromised saliva secretion.
• Infections (primarily candidiasis).
• Tissue necrosis (soft tissue necrosis and osteonecrosis).
• Taste dysfunction (dysgeusia/ageusia).
• Muscular and cutaneous fibrosis.[1]
• Dysphagia.[2]

Management of oral mucositis

The etiopathogenesis of mucositis caused by head and neck radiation appears to be similar but not identical to mucositis caused by high-dose chemotherapy.[3,4,5] Management strategies described for chemotherapy/hematopoietic stem cell transplantation are generally applicable to the head/neck radiation patient.[6,7] (Refer to the Management of mucositis section of this summary for more information.) In one study, gabapentin appeared promising in reducing the need for narcotic pain medication for patients with head and neck malignancies treated with radiation therapy.[8][Level of evidence: III]

The extensive duration and severity of radiation mucositis combined with the treatment of most radiation patients as outpatients results in pain management challenges. As mucositis severity increases and topical pain management strategies become less effective, it becomes increasingly necessary to depend on systemic analgesics to manage oral radiation mucositis pain:[9]

• Because there is generally no risk of bleeding for head and neck radiation patients, analgesic treatment begins with nonsteroidal anti-inflammatory drugs (NSAIDs).
• As pain increases, NSAIDs are combined with opioids, and patients can be made relatively comfortable.

Doses for NSAIDs are titrated up to their recommended dosing ceiling; on the other hand, opioids are titrated to effective pain relief. Systemic analgesics are given by the clock to achieve steady-state blood levels to provide adequate pain relief.

Additionally, adjunctive medications are given to provide adjuvant analgesia and manage side effects of NSAIDs and opioids. Zinc supplementation used with radiation therapy may improve mucositis and dermatitis.[10][Level of evidence: I] The use of alcohol-free povidone-iodine mouthwash may reduce the severity and delay the onset of oral mucositis caused by antineoplastic radiation therapy.[11][Level of evidence: I]

Early infections

A systematic review indicated that the weighted mean prevalence of clinical oral candidiasis during head and neck radiation therapy is 37.4% and may be significantly higher in patients who receive concurrent chemotherapy.[12] Factors promoting clinical fungal infection in this population include the following:

• Hyposalivation resulting from radiation damage to the salivary glands.
• Tissue damage caused by radiation-induced oral mucositis.
• Resulting dietary impairment.
• Inability to maintain oral hygiene.

Because these patients are usually not significantly neutropenic, topical antifungal agents such as nystatin rinse/pastilles and clotrimazole troches can be effective. The use of a troche may be limited by significant xerostomia. Patients who receive topical antifungals should be asked to avoid eating, drinking, or rinsing for at least 30 minutes after use. Patients with removable dentures should remove the dentures before using the topical antifungals and should also treat the dentures to avoid repeat colonization of the oral tissues by fungal organisms that are colonizing the dentures.

For persistent lesions, systemic agents such as fluconazole are very effective.

Taste dysfunction

As oral and pharyngeal mucosa are exposed to radiation, taste receptors become damaged, and taste discrimination becomes increasingly compromised.[13,14] After several weeks of radiation therapy, patients commonly complain that they have no sense of taste. It will generally take 6 to 8 weeks after the end of radiation therapy for taste receptors to recover and become functional. Zinc sulfate supplements (220 mg 2 or 3 times a day) have been reported to help with recovery of the sense of taste.[15,16][Level of evidence: I]

References:

1. Vera-Llonch M, Oster G, Hagiwara M, et al.: Oral mucositis in patients undergoing radiation treatment for head and neck carcinoma. Cancer 106 (2): 329-36, 2006.
2. Caudell JJ, Schaner PE, Meredith RF, et al.: Factors associated with long-term dysphagia after definitive radiotherapy for locally advanced head-and-neck cancer. Int J Radiat Oncol Biol Phys 73 (2): 410-5, 2009.
3. Sonis ST: Mucositis as a biological process: a new hypothesis for the development of chemotherapy-induced stomatotoxicity. Oral Oncol 34 (1): 39-43, 1998.
4. Sonis ST, Peterson DE, McGuire DB, eds.: Mucosal injury in cancer patients: new strategies for research and treatment. J Natl Cancer Inst Monogr (29): 1-54, 2001.
5. Barasch A, Peterson DE: Risk factors for ulcerative oral mucositis in cancer patients: unanswered questions. Oral Oncol 39 (2): 91-100, 2003.
6. Demarosi F, Bez C, Carrassi A: Prevention and treatment of chemo- and radiotherapy-induced oral mucositis. Minerva Stomatol 51 (5): 173-86, 2002.
7. Shih A, Miaskowski C, Dodd MJ, et al.: A research review of the current treatments for radiation-induced oral mucositis in patients with head and neck cancer. Oncol Nurs Forum 29 (7): 1063-80, 2002.
8. Bar Ad V, Weinstein G, Dutta PR, et al.: Gabapentin for the treatment of pain related to radiation-induced mucositis in patients with head and neck tumors treated with intensity-modulated radiation therapy. Head Neck 32 (2): 173-7, 2010.
9. Wong PC, Dodd MJ, Miaskowski C, et al.: Mucositis pain induced by radiation therapy: prevalence, severity, and use of self-care behaviors. J Pain Symptom Manage 32 (1): 27-37, 2006.
10. Lin LC, Que J, Lin LK, et al.: Zinc supplementation to improve mucositis and dermatitis in patients after radiotherapy for head-and-neck cancers: a double-blind, randomized study. Int J Radiat Oncol Biol Phys 65 (3): 745-50, 2006.
11. Madan PD, Sequeira PS, Shenoy K, et al.: The effect of three mouthwashes on radiation-induced oral mucositis in patients with head and neck malignancies: a randomized control trial. J Cancer Res Ther 4 (1): 3-8, 2008 Jan-Mar.
12. Lalla RV, Latortue MC, Hong CH, et al.: A systematic review of oral fungal infections in patients receiving cancer therapy. Support Care Cancer 18 (8): 985-92, 2010.
13. Nelson GM: Biology of taste buds and the clinical problem of taste loss. Anat Rec 253 (3): 70-8, 1998.
14. Zheng WK, Inokuchi A, Yamamoto T, et al.: Taste dysfunction in irradiated patients with head and neck cancer. Fukuoka Igaku Zasshi 93 (4): 64-76, 2002.
15. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28.
16. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998.

Late Complications of Head and Neck Radiation

Late oral complications of radiation therapy are chiefly a result of chronic injury to vasculature, salivary glands, mucosa, connective tissue, and bone.[1,2,3,4] The types and severity of these changes are directly related to radiation dosimetry, including total dose, fraction size, and duration of treatment.

Mucosal Lesions

Mucosal lesions include epithelial atrophy, reduced vascularization, and submucosal fibrosis. These changes lead to an atrophic, friable barrier. Fibrosis involving muscle, dermis, and the temporomandibular joint results in compromised oral function. Salivary tissue changes include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. Compromised vascularization and remodeling capacity of bone leads to risk of osteonecrosis.

Salivary Gland Hypofunction and Xerostomia

Ionizing radiation to salivary glands results in inflammatory and degenerative effects on salivary gland parenchyma, especially serous acinar cells. The early salivary gland tissue response to irradiation results in decreased salivary flow rates within the first week of treatment, and xerostomia (the subjective feeling of oral dryness) becomes apparent when doses exceed 10 Gy.

The degree of dysfunction is related to the radiation dose and volume of glandular tissue in the radiation field. Doses larger than 54 Gy are generally considered to induce irreversible dysfunction. Serous parotid glands may be more susceptible to radiation effects than are nonserous submandibular, sublingual, and minor salivary gland tissues. Management strategies described for late salivary gland complications are generally applicable to the acute complications in the head/neck radiation patient. (Refer to the Oral and dental management of the xerostomic patient section of this summary for more information.)

Salivary gland hypofunction (decreased salivary gland secretion) and xerostomia are among the most frequent and severe long-term side effects of radiation therapy to the head and neck region. The adverse effects will have a significant impact on a patient's quality of life in a lifelong perspective after radiation treatment.[5]

Xerostomia is caused by salivary gland hypofunction. Saliva is necessary for the normal execution of oral functions such as taste, swallowing, and speech. Unstimulated whole salivary flow rates lower than 0.1 mL per minute are considered pathologic low (normal salivary flow rate = 0.3-0.5 mL/min).[6]

Late salivary tissue changes induced by radiation therapy include loss of acinar cells, alteration in duct epithelium, fibrosis, and fatty degeneration. The early response to irradiation resulting in markedly decreased salivary flow rates within the first week of treatment is followed by a further decline in saliva secretion and worsening of xerostomia after radiation therapy (1-3 months posttreatment), whereafter salivary secretion and xerostomia gradually recover over time (maximum recovery, 1-2 years posttherapy), depending on the total radiation dose to the gland tissue.[6] Recovery of salivary gland function is usually incomplete, and the overall degree of dryness can range from mild to severe.

It should be noted that salivary gland hypofunction and xerostomia may also be sequelae of other radiation regimens, e.g., radioactive iodine treatment of thyroid cancer and preconditioning total body irradiation in hematopoietic stem cell transplantation for the treatment of hematologic malignancies-although to a much lesser severity.[7,8]

Symptoms and signs of salivary gland hypofunction include the following:

• Xerostomia.
• Lip dryness/crusting.
• Fissures at lip commissures.
• Atrophy of dorsal tongue surface.
• Atrophic and fragile oral mucosa.
• Difficulties in speech, chewing, and swallowing.
• Difficulty in wearing dentures (edentulous patients).
• Oral burning sensation.
• Taste disturbances.
• Increased thirst.
• Sensitivity/pain in response to spicy foods and strong flavorings.

Salivary gland tissues that have been excluded from the radiation portal may become hyperplastic, partially compensating for the nonfunctional glands at other oral sites.

Salivary gland hypofunction also alters the mechanical cleansing ability and the buffer capacity of the mouth, thereby contributing to a high risk of accelerated dental caries (cavities) and periodontal disease. Also, the progression of dental caries is accelerated by the reduction in antimicrobial proteins normally contained in saliva.

In summary, salivary gland hypofunction produces the following changes in the mouth that collectively cause patient discomfort and increased risk of oral lesions:

• Increase in salivary viscosity, with resultant impaired lubrication of oral tissues.
• Decrease in flushing/clearance of acid production after sugar exposure, resulting in demineralization of the teeth and leading to dental decay.
• Compromise of buffering capacity and salivary pH, with increased risk for dental caries and erosion.
• Increase in pathogenicity of oral flora.
• Accumulated bacterial plaque levels caused by patient difficulty in maintaining oral hygiene (caused by soreness of oral mucosa and/or muscular fibrosis/trismus).

Oral and dental management of the xerostomic patient

Patients who experience salivary gland hypofunction and xerostomia must maintain excellent oral hygiene to minimize the risk of oral lesions. Periodontal disease can be accelerated and caries can become rampant unless preventive measures are instituted. Multiple preventive strategies should be considered.

Oral hygiene protocol

Perform systematic oral hygiene at least 4 times per day (after meals and at bedtime):

• Brush teeth (if soreness of oral mucosa and trismus are present, use small ultrasoft toothbrush).
• Use a fluoridated toothpaste when brushing.
• Floss once daily.
• Apply a prescription-strength fluoride gel at bedtime to prevent caries.
• Rinse with a solution of salt and baking soda 4 to 6 times a day (½ tsp salt and ½ tsp baking soda in 1 c warm water) to clean and lubricate the oral tissues and to buffer the oral environment.
• Sip water frequently to rinse the mouth and alleviate mouth dryness.
• Avoid foods and liquids with a high sugar content. (Refer to the PDQ summary on Nutrition in Cancer Care for more information.)

Fluorides

Prescription-strength fluorides should be used because nonprescription fluoride preparations are inadequate for moderate to high risk of dental caries. If drinking water does not contain enough fluoride to prevent dental decay, oral fluoride (e.g., drops or vitamins) should be provided.

Use of topical fluoride has demonstrable benefit in minimizing caries formation. During radiation treatment, it has been recommended that mouth guards be filled with topical 1% sodium fluoride gel and placed over the upper and lower teeth. The appliances should remain in place for 5 minutes, after which the patient should not eat or drink for 30 minutes.

Remineralizing solutions:

• Fluoride and calcium/phosphates.
• Topical high-concentration fluorides.
• Children: topical and systemic.
• Adults: topical.

Management of xerostomia

Prevention of salivary gland hypofunction and xerostomia

To prevent or reduce the extent of salivary gland hypofunction and xerostomia, parotid-sparing intensity-modulated radiation therapy (IMRT) is recommended as a standard approach in head and neck cancer (HNC), if oncologically feasible. In addition, treatment should focus on approaches to further reduce the radiation dose to the submandibular and minor salivary glands, as these glands are the major contributors to moistening of oral tissues.[9]

Another preventive strategy to reduce radiation-induced salivary gland hypofunction and xerostomia is surgical transfer of one submandibular gland to the submental space not included in the radiation portal in selected oropharyngeal and hypopharyngeal/laryngeal cancer patients.[10];[11][Level of evidence: I]

Amifostine is an organic thiophosphate approved for the protection of normal tissues against the harmful effects of radiation or chemotherapy, including reduction of acute or late xerostomia in patients with HNC. Studies have reported varying degrees of effectiveness.[12,13][Level of evidence: I] One randomized prospective study reported that intravenous amifostine administered during head and neck radiation therapy reduces the severity and duration of xerostomia 2 years after amifostine treatment, without apparent compromise of locoregional tumor control rates, progression-free survival, or overall patient survival.[14][Level of evidence: I] The intravenous administration of amifostine may cause severe adverse effects such as hypotension, vomiting, nausea, and allergic reaction. These adverse effects might be reduced by subcutaneous administration of amifostine. The possible risk of tumor protection by amifostine remains a clinical concern.[15]

Alleviation of xerostomia

Treatment of salivary gland hypofunction and xerostomia induced by radiation therapy is primarily symptomatic. Alleviation of xerostomia includes frequent sipping or spraying of the oral cavity with water, the use of saliva substitutes, or stimulation of saliva production from intact salivary glandular tissues by taste/mastication, pharmacological sialogogues, or acupuncture.[9]

Saliva substitutes or artificial saliva preparations (e.g., oral rinses or gels containing hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylcellulose, polyglycerylmethacrylate, mucin, or xanthan gum) are palliative agents that relieve the discomfort of xerostomia by temporarily wetting the oral mucosa.[9]

Sugar-free lozenges, acidic candies, or chewing gum may produce transitory relief from xerostomia by stimulating residual capacity of salivary gland tissue (acidic products can result in demineralization of the teeth and may not be recommended in dentate patients).[9]

Pilocarpine is the only drug approved by the U.S. Food and Drug Administration for use as a sialogogue (5-mg tablets of pilocarpine hydrochloride) for radiation xerostomia. Treatment is initiated at 5 mg by mouth 3 times a day; the dose is then titrated to achieve optimal clinical response and minimize adverse effects. Some patients may experience increased benefit at higher daily doses; however, incidence of adverse effects increases proportionally with dose. The patient's evening dose may be increased to 10 mg within 1 week after starting pilocarpine. Subsequently, morning and afternoon doses may also be increased to a maximum 10 mg per dose (30 mg/d). Patient tolerance is confirmed by allowing 7 days between increments.

The most common adverse effect at clinically useful doses of pilocarpine is hyperhidrosis (excessive sweating); its incidence and severity are proportional to dosage. Also reported, typically at doses higher than 5 mg 3 times a day, are the following:

• Nausea.
• Chills.
• Rhinorrhea.
• Vasodilation.
• Increased lacrimation.
• Bladder pressure (urinary urgency and frequency).
• Dizziness.
• Asthenia.
• Headache.
• Diarrhea.
• Dyspepsia.

Pilocarpine usually increases salivary flow within 30 minutes after ingestion. Maximal response may occur only after continual use (>8 weeks).[16][Level of evidence: I]

It has been suggested that pilocarpine given during radiation therapy may reduce salivary gland impairment and xerostomia both during and after treatment. However, in a randomized study of 249 patients with HNC, the concomitant use of pilocarpine during radiation did not have a positive impact on quality of life or patient assessment of salivary function, despite the maintenance of salivary flow.[17][Level of evidence: I] It has been indicated that the efficacy of pilocarpine depends on the radiation dose distributed to the parotid glands during treatment, i.e., in patients in whom the mean parotid dose exceeds 40 Gy, pilocarpine may spare parotid gland function and reduce xerostomia-particularly significant after 12 months.[18][Level of evidence: I]

Cevimeline (30 mg 3 times a day) also appears anecdotally to have efficacy in managing radiation-induced xerostomia.[19];[20][Level of evidence: I] Although cevimeline is approved for use only in the management of Sjögren syndrome, appropriate clinical trials are under way, and its efficacy should be established soon. While cevimeline has greater selective affinity for M3 muscarinic receptors than pilocarpine, whether this can prove advantageous for treating radiation xerostomia remains unclear.

Acupuncture appears to offer an intervention for the treatment of radiation-induced xerostomia in patients with a residual functional capacity of the salivary glands and is a treatment modality without serious adverse effects.[21,22,23] Further randomized controlled clinical trials, including sham acupuncture, are warranted.

Intraoral electrical stimulation devices delivering a low-intensity electrical current to the oral mucosa-thus stimulating salivary gland secretion by innervating afferent neurons of the salivary reflex and efferent neurons (e.g., the lingual nerve)-is under development and has been tested, with promising initial results in the palliation of xerostomia.[24];[25] Special considerations appear to be indicated when electrostimulation devices are used in head and neck radiation patients.[26][Level of evidence: I] Further studies are needed.

Caries

The risk of dental caries increases secondary to a number of factors, including shifts to a cariogenic flora, reduced concentrations of salivary antimicrobial proteins, and loss of mineralizing components.[3] (Refer to the Conditions Affected By Both Chemotherapy and Head/Neck Radiation section of this summary for more information.) As reported in a systematic review, the overall count of decayed, missing, or filled teeth (DMFT) in patients who were post-antineoplastic therapy was 9.19 (standard deviation [SD], 7.98; n = 457). The DMFT for patients who were post-radiation therapy was 17.01 (SD, 9.14; n = 157), which was much higher than that in patients who were postchemotherapy (DMFT, 4.5).[27]

Treatment strategies must be directed to each component of the caries process. Optimal oral hygiene must be maintained. Xerostomia should be managed whenever possible via salivary substitutes or replacements. Caries resistance can be enhanced with the use of topical fluorides and/or remineralizing agents. Efficacy of topical products may be enhanced by increased contact time on the teeth by application using vinyl carriers. Patients unable to effectively comply with use of fluoride trays should be instructed to use brush-on gels and rinses.

Increased colonization with Streptococcus mutans and Lactobacillus species increases caries risk. Culture data can be useful in defining level of risk in relation to colonization patterns. Topical fluorides or chlorhexidine rinses may lead to reduced levels of S. mutans but not Lactobacilli. Because of adverse drug interactions, fluoride and chlorhexidine dosing should be separated by several hours.

Remineralizing agents, which are high in calcium phosphate and fluoride, have demonstrated salutary in vitro and clinical effects. The intervention may be enhanced by delivering the drug via customized vinyl carriers. This approach extends the contact time of active drug with tooth structure, which leads to increased uptake into enamel.

A systematic review of managing dental caries in post-radiation therapy patients produced the following conclusions:[27,28]

• Fluoride: The use of fluoride products reduces caries activity in patients who are post-radiation therapy. The type of fluoride gel or fluoride delivery system used did not significantly influence caries activity.
• Chlorhexidine: The use of chlorhexidine rinse reduces plaque scores and oral streptococcus mutans scores. This reduction was not seen with lactobacillus counts.
• Dental restorative materials: There is evidence suggesting that conventional glass ionomer restorations performed more poorly than did resin-modified glass ionomer, composite resin, and amalgam restorations in patients who had been treated with radiation therapy.

Osteoradionecrosis

Risk of osteoradionecrosis (ORN) is directly related to radiation dose and volume of tissue irradiated. The unilateral vascular supply to each half of the mandible results in postradiation ORN most frequently involving the mandible, compared with the maxilla. Presenting clinical features include:

• Pain.
• Diminished or complete loss of sensation.
• Fistula.
• Infection.

Pathologic fracture can occur because the compromised bone is unable to appropriately undergo repair at the involved sites. Risk of tissue necrosis is in part related to trauma or oral infection; however, idiopathic cases can also occur. Patients who have received high-dose radiation to the head and neck are at lifelong risk for ORN, with an overall risk of approximately 15%.

Ideally, postradiation management or ORN is based on prevention that begins with comprehensive oral and dental care before radiation therapy begins. The dentition, periodontium, periapices, and mucosa should be thoroughly examined to identify oral disease, which could lead to serious odontogenic, periodontal, or mucosal infections that could necessitate surgical therapy postradiation. Oral disease should be eliminated pretreatment. Dentition that exhibits poor prognosis and is within high-dose fields should be extracted before radiation therapy begins. Ideally, at least 7 to 14 days should be allowed for healing before initiation of radiation; some have suggested allowing up to 21 days. Surgical technique should be as atraumatic as possible and use primary wound closure.

Patients who develop ORN should be comprehensively managed to:

• Eliminate trauma.
• Avoid removable dental prosthesis if the denture-bearing area is within the osteonecrotic field.
• Ensure adequate nutritional intake.
• Discontinue tobacco and alcohol use.

Topical antibiotics (e.g., tetracycline) or antiseptics (e.g., chlorhexidine) may contribute to wound resolution. Wherever possible, coverage of the exposed bone with mucosa should be achieved. Analgesics for pain control are often effective. Local resection of bone sequestra may be possible.

Hyperbaric oxygen therapy (HBO) is recommended for management of ORN, although it has not been universally accepted. HBO has been reported to increase oxygenation of irradiated tissue, promote angiogenesis, and enhance osteoblast repopulation and fibroblast function. HBO is usually prescribed as 20 to 30 dives at 100% oxygen and 2 to 2.5 atmospheres of pressure. If surgery is needed, ten dives of postsurgical HBO are recommended. Unfortunately, HBO technology is not always accessible to patients who might otherwise benefit because of lack of available units and the high price of care.

A systematic review regarding treatment-dependent frequency, current management strategies, and future studies has been published.[29] A total of 43 articles published between 1990 and 2008 were reviewed. The weighted prevalence for ORN included the following:

• Conventional radiation therapy, 7.4%.
• IMRT, 5.1%.
• Chemoradiation therapy, 6.8%.
• Brachytherapy, 5.3%.

HBO may contribute a role in management of ORN. However, no clear recommendations for the prevention or treatment of ORN could be established on the basis of the literature reviewed. The review concluded that new cancer treatment modalities such as IMRT and concomitant chemoradiation therapy have had minimal effect on prevalence of ORN. No studies have systematically addressed the impact of ORN on either quality of life or cost of care. Research addressing these collective issues is needed.

Partial mandibulectomy may be necessary in severe cases of ORN. The mandible can be reconstructed to provide continuity for esthetics and function. A multidisciplinary cancer team that includes oncologists, oncology nurses, maxillofacial prosthodontists, general dentists, hygienists, and physical therapists is appropriate for management of these patients.

Tissue Necrosis

Necrosis and secondary infection of previously irradiated tissue is a serious complication for patients who have undergone radiation therapy for head and neck tumors.[3] Acute effects typically involve oral mucosa. Chronic changes involving bone and mucosa are a result of the process of vascular inflammation and scarring that in turn result in hypovascular, hypocellular, and hypoxic changes. Infection secondary to tissue injury and osteonecrosis confounds the process.

Soft tissue necrosis can involve any mucosal surface in the mouth, though nonkeratinized surfaces appear to be at moderately higher risk. Trauma and injury are often associated with nonhealing soft tissue necrotic lesions, though spontaneous lesions are also reported. Soft tissue necrosis begins as an ulcerative break in the mucosal surface and can spread in diameter and depth. Pain will generally become more prominent as soft tissue necrosis becomes worse. Secondary infection is a risk.

Mandibular Dysfunction

Musculoskeletal syndromes may develop secondary to radiation therapy and surgery. Lesions include soft tissue fibrosis, surgically induced mandibular discontinuity, and parafunctional habits associated with emotional stress caused by cancer and its treatment. Patients can be instructed in physical therapy interventions such as mandibular stretching exercises and the use of prosthetic aids designed to reduce the severity of fibrosis. It is important that these approaches be instituted before trismus develops. If clinically significant changes develop, several approaches can be considered, including the following:

• Stabilization of occlusion.
• Use of trigger-point injection and other pain management strategies.
• Use of muscle relaxants.
• Use of tricyclic medications.

Trismus

Trismus has been associated with significant morbidity post-radiation therapy, with significant health implications, including reduced nutrition due to impaired mastication, difficulty in speaking, and compromised oral hygiene.[30] Limitations in jaw opening have been reported in 6% to 86% of patients who received radiation to the temporomandibular joint and/or masseter/pterygoid muscles, with frequency and severity that are somewhat unpredictable.[31]

The loss of function and range of mandibular motion from radiation therapy appears to be related to fibrosis in and damage to the muscles of mastication. Studies have demonstrated that an abnormal proliferation of fibroblasts is an important initial event in these reactions. Additionally, there may be scar tissue from radiation therapy or surgery, nerve damage, or a combination of these factors. Regardless of the immediate cause, mandibular hypomobility will ultimately result in degeneration of both muscle and temporomandibular joint.

Radiation therapy involving the temporomandibular joint, the pterygoid muscles, or the masseter muscle is most likely to result in trismus.[30] Tumors related to this type of radiation can appear in the following locations:

• Nasopharynx.
• Oral cavity.
• Oropharynx.
• Base of tongue.
• Salivary gland.
• Maxilla or mandible.

The prevalence of trismus increases with increasing doses of radiation, and levels in excess of 60 Gy are more likely to cause trismus.[5] Patients who have been previously irradiated and who are being treated for a recurrence appear to be at higher risk of trismus than those who are receiving their first treatment.[32,33] This suggests that the effects of radiation are cumulative, even over many years. Radiation-induced trismus may begin toward the end of radiation therapy or at any time during the subsequent 24 months. Limitations in opening the mouth often increase slowly over several weeks or months. The condition may worsen over time or remain the same, or the symptoms may reduce over time, even in the absence of treatment.

Limited mouth opening frequently results in reduced nutritional status. These patients may experience significant weight loss and nutritional deficits.[34] It is generally accepted that weight loss of more than 10% of initial body weight is considered significant. This is of particular importance at a time when the patient is recovering from surgery, chemotherapy, and/or radiation therapy. Additionally, it lowers the ability for social eating and thereby increases the risk of social isolation and decrease in quality of life in patients with HNC.

Finally, limited mouth opening can result in compromised oral hygiene. Patients who have undergone radiation therapy involving the salivary glands must maintain excellent oral hygiene to prevent dental caries. Deficits in oral hygiene can aggravate mucosal and dental problems, with the subsequent risk of mandibular ORN. Also, dental work and other professional oral care measures such as surgery can be made more difficult, which might even result in compromised oncologic follow-up.

The weighted prevalence of trismus with conventional radiation is estimated to be 25%, but 5% with IMRT only. Trismus prevalence in studies of chemoradiation is approximately 30%.[35]

Prevention strategies

Early treatment of trismus has the potential to prevent or minimize many of the consequences of this condition. If the clinical examination reveals the presence of limited mouth opening, and diagnosis determines the condition to be trismus, treatment should begin as soon as is practical. As restriction becomes more severe and likely irreversible, the need for treatment becomes more urgent.

Over the years, clinicians have attempted to prevent or treat trismus with a wide array of appliances. These devices include the following:

• Cages that fit over the head.
• Heavy springs that fit between the teeth.
• Screws that are placed between the central incisors.
• Hydraulic bulbs placed between the teeth.

These devices range widely in cost. Some devices, such as continuous passive motion devices, must be custom made for each patient; others are rented on a daily or weekly basis, at rates of up to several hundred dollars per week. The least expensive option is the use of tongue depressors, which has been used for many years to mobilize the jaw. A search of the literature, however, failed to reveal any studies that demonstrated significant improvement in treating trismus with tongue depressors.

Curative approach

Some therapeutic interventions seem to show some efficacy in decreasing the intensity of cancer treatment-related trismus (e.g., pentoxifylline,[36,37] Botulinum toxin,[38] exercise using the Therabite device,[39] and the Dynasplint Trismus System [40]). However, this proposed efficacy must be confirmed by randomized controlled studies, which are lacking in this area.

Recommendations for future research directions

Radiation oncology textbooks often fail to mention trismus as a sequela of radiation therapy for HNC patients, contributing to a lack of recognition of the prevalence and significance of this condition. There has been an ongoing attempt by the Radiation Therapy Oncology Group and the European Organization for Research and Treatment of Cancer to develop LENT (late effects in normal tissue) morbidity scales. The National Cancer Institute consensus conferences introduced the SOMA (subjective, objective, management, analysis) classification for late toxicity. However, both scales are focused on major organ and dermatological injuries, and trismus is not addressed. This should be corrected in future revisions of these scales.

Considering the high prevalence of trismus in published studies and the deficits in quality of life associated with trismus, increased efforts for patient education, prevention, and early treatment options are warranted. Larger prospective trials that include the prevention and treatment of trismus are needed to improve management and to confirm the benefit of IMRT in the reduction of radiation-induced trismus and the quality-of-life and economic impact of this common oral sequela of radiation.

Current Clinical Trials

Check the list of NCI-supported cancer clinical trials for supportive and palliative care trials about xerostomia that are now accepting participants. The list of trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI website.

References:

1. Myers RA, Marx RE: Use of hyperbaric oxygen in postradiation head and neck surgery. NCI Monogr (9): 151-7, 1990.
2. Epstein JB, Wong FL, Stevenson-Moore P: Osteoradionecrosis: clinical experience and a proposal for classification. J Oral Maxillofac Surg 45 (2): 104-10, 1987.
3. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28.
4. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010.
5. Teguh DN, Levendag PC, Voet P, et al.: Trismus in patients with oropharyngeal cancer: relationship with dose in structures of mastication apparatus. Head Neck 30 (5): 622-30, 2008.
6. Jellema AP, Slotman BJ, Doornaert P, et al.: Impact of radiation-induced xerostomia on quality of life after primary radiotherapy among patients with head and neck cancer. Int J Radiat Oncol Biol Phys 69 (3): 751-60, 2007.
7. Hyer S, Kong A, Pratt B, et al.: Salivary gland toxicity after radioiodine therapy for thyroid cancer. Clin Oncol (R Coll Radiol) 19 (1): 83-6, 2007.
8. Dahllöf G, Bågesund M, Ringdén O: Impact of conditioning regimens on salivary function, caries-associated microorganisms and dental caries in children after bone marrow transplantation. A 4-year longitudinal study. Bone Marrow Transplant 20 (6): 479-83, 1997.
9. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: management strategies and economic impact. Support Care Cancer 18 (8): 1061-79, 2010.
10. Seikaly H, Jha N, Harris JR, et al.: Long-term outcomes of submandibular gland transfer for prevention of postradiation xerostomia. Arch Otolaryngol Head Neck Surg 130 (8): 956-61, 2004.
11. Jha N, Seikaly H, Harris J, et al.: Phase III randomized study: oral pilocarpine versus submandibular salivary gland transfer protocol for the management of radiation-induced xerostomia. Head Neck 31 (2): 234-43, 2009.
12. Buentzel J, Micke O, Adamietz IA, et al.: Intravenous amifostine during chemoradiotherapy for head-and-neck cancer: a randomized placebo-controlled phase III study. Int J Radiat Oncol Biol Phys 64 (3): 684-91, 2006.
13. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006.
14. Wasserman TH, Brizel DM, Henke M, et al.: Influence of intravenous amifostine on xerostomia, tumor control, and survival after radiotherapy for head-and- neck cancer: 2-year follow-up of a prospective, randomized, phase III trial. Int J Radiat Oncol Biol Phys 63 (4): 985-90, 2005.
15. Brizel DM, Overgaard J: Does amifostine have a role in chemoradiation treatment? Lancet Oncol 4 (6): 378-81, 2003.
16. Rieke JW, Hafermann MD, Johnson JT, et al.: Oral pilocarpine for radiation-induced xerostomia: integrated efficacy and safety results from two prospective randomized clinical trials. Int J Radiat Oncol Biol Phys 31 (3): 661-9, 1995.
17. Scarantino C, LeVeque F, Swann RS, et al.: Effect of pilocarpine during radiation therapy: results of RTOG 97-09, a phase III randomized study in head and neck cancer patients. J Support Oncol 4 (5): 252-8, 2006.
18. Burlage FR, Roesink JM, Kampinga HH, et al.: Protection of salivary function by concomitant pilocarpine during radiotherapy: a double-blind, randomized, placebo-controlled study. Int J Radiat Oncol Biol Phys 70 (1): 14-22, 2008.
19. Chambers MS, Jones CU, Biel MA, et al.: Open-label, long-term safety study of cevimeline in the treatment of postirradiation xerostomia. Int J Radiat Oncol Biol Phys 69 (5): 1369-76, 2007.
20. Jham BC, Teixeira IV, Aboud CG, et al.: A randomized phase III prospective trial of bethanechol to prevent radiotherapy-induced salivary gland damage in patients with head and neck cancer. Oral Oncol 43 (2): 137-42, 2007.
21. Blom M, Lundeberg T: Long-term follow-up of patients treated with acupuncture for xerostomia and the influence of additional treatment. Oral Dis 6 (1): 15-24, 2000.
22. O'Sullivan EM, Higginson IJ: Clinical effectiveness and safety of acupuncture in the treatment of irradiation-induced xerostomia in patients with head and neck cancer: a systematic review. Acupunct Med 28 (4): 191-9, 2010.
23. Cho JH, Chung WK, Kang W, et al.: Manual acupuncture improved quality of life in cancer patients with radiation-induced xerostomia. J Altern Complement Med 14 (5): 523-6, 2008.
24. Strietzel FP, Martín-Granizo R, Fedele S, et al.: Electrostimulating device in the management of xerostomia. Oral Dis 13 (2): 206-13, 2007.
25. Strietzel FP, Lafaurie GI, Mendoza GR, et al.: Efficacy and safety of an intraoral electrostimulation device for xerostomia relief: a multicenter, randomized trial. Arthritis Rheum 63 (1): 180-90, 2011.
26. Lafaurie G, Fedele S, López RM, et al.: Biotechnological advances in neuro-electro-stimulation for the treatment of hyposalivation and xerostomia. Med Oral Patol Oral Cir Bucal 14 (2): E76-80, 2009.
27. Hong CH, Napeñas JJ, Hodgson BD, et al.: A systematic review of dental disease in patients undergoing cancer therapy. Support Care Cancer 18 (8): 1007-21, 2010.
28. Brennan MT, Elting LS, Spijkervet FK: Systematic reviews of oral complications from cancer therapies, Oral Care Study Group, MASCC/ISOO: methodology and quality of the literature. Support Care Cancer 18 (8): 979-84, 2010.
29. Peterson DE, Doerr W, Hovan A, et al.: Osteoradionecrosis in cancer patients: the evidence base for treatment-dependent frequency, current management strategies, and future studies. Support Care Cancer 18 (8): 1089-98, 2010.
30. Dijkstra PU, Kalk WW, Roodenburg JL: Trismus in head and neck oncology: a systematic review. Oral Oncol 40 (9): 879-89, 2004.
31. Louise Kent M, Brennan MT, Noll JL, et al.: Radiation-induced trismus in head and neck cancer patients. Support Care Cancer 16 (3): 305-9, 2008.
32. Dijkstra PU, Huisman PM, Roodenburg JL: Criteria for trismus in head and neck oncology. Int J Oral Maxillofac Surg 35 (4): 337-42, 2006.
33. Yeh SA, Tang Y, Lui CC, et al.: Treatment outcomes and late complications of 849 patients with nasopharyngeal carcinoma treated with radiotherapy alone. Int J Radiat Oncol Biol Phys 62 (3): 672-9, 2005.
34. Hsiung CY, Huang EY, Ting HM, et al.: Intensity-modulated radiotherapy for nasopharyngeal carcinoma: the reduction of radiation-induced trismus. Br J Radiol 81 (970): 809-14, 2008.
35. Bensadoun RJ, Riesenbeck D, Lockhart PB, et al.: A systematic review of trismus induced by cancer therapies in head and neck cancer patients. Support Care Cancer 18 (8): 1033-8, 2010.
36. Chua DT, Lo C, Yuen J, et al.: A pilot study of pentoxifylline in the treatment of radiation-induced trismus. Am J Clin Oncol 24 (4): 366-9, 2001.
37. Grandi G, Silva ML, Streit C, et al.: A mobilization regimen to prevent mandibular hypomobility in irradiated patients: an analysis and comparison of two techniques. Med Oral Patol Oral Cir Bucal 12 (2): E105-9, 2007.
38. Hartl DM, Cohen M, Juliéron M, et al.: Botulinum toxin for radiation-induced facial pain and trismus. Otolaryngol Head Neck Surg 138 (4): 459-463, 2008.
39. Melchers LJ, Van Weert E, Beurskens CH, et al.: Exercise adherence in patients with trismus due to head and neck oncology: a qualitative study into the use of the Therabite. Int J Oral Maxillofac Surg 38 (9): 947-54, 2009.
40. Shulman DH, Shipman B, Willis FB: Treating trismus with dynamic splinting: a cohort, case series. Adv Ther 25 (1): 9-16, 2008.

Conditions Affected By Both Chemotherapy and Head / Neck Radiation

Salivary Gland Hypofunction and Xerostomia

Radiation therapy can damage salivary glands, causing salivary hypofunction and xerostomia. (Refer to the Oral Complications of Head and Neck Radiation section of this summary for more information.) In addition, selected chemotherapeutic agents (singly or in combination) have been implicated in causing salivary dysfunction and xerostomia.[1] However, it has not been possible to draw consistent conclusions about the effects of cancer chemotherapy on salivary gland function.[2]

Dysphagia

Dysphagia and odynophagia are common in cancer patients and can exist before, during, and after treatment:

• Dysphagia predisposes to aspiration and potentially life-threatening pulmonary complications.[3]
• Swallowing disorders may lead to unfavorable dietary changes and decreased oral intake, which may result in dehydration, malnutrition, delayed wound healing, and decreased resistance to infection.
• Tube feeding may become necessary, which may further compromise swallowing.
• Opioids administered for the management of odynophagia may cause xerostomia and constipation.
• Difficulties with speaking, eating and drinking, or drooling may affect mental health and put patients and family members in social isolation.

All of these problems, plus the patient perception of swallowing difficulties, significantly decrease health-related quality of life.[3,4]

Dysphagia is most prominent in patients with head and neck cancers but may also develop in patients with other malignancies as a symptom of oropharyngeal or esophageal mucositis or infection. In addition, dysphagia can be associated with graft-versus-host disease.

The prevalence and severity of pretreatment dysphagia associated with head and neck tumors depend on tumor stage and localization.[5] Pretreatment dysphagia is most prevalent in patients with pharyngeal and laryngeal cancers.[6] Surgical interventions for head and neck tumors result in anatomic or neurologic insults with site-specific patterns of dysphagia.[7] In general, the larger the resection, the more swallowing function will be impaired.

The severity of radiation-induced dysphagia depends on the following:[8]

• Total radiation dose.
• Fraction size and schedule.
• Target volumes.
• Treatment delivery techniques.
• Concurrent chemotherapy.
• Genetic factors.
• Feeding status (via percutaneous endoscopic gastrostomy [PEG] tube or nil per os [NPO, nothing by mouth]).
• Smoking status.
• Psychological coping factors.

Intensified schedules and the use of chemoradiation therapy have been shown to improve locoregional control and survival but come at the cost of more severe acute and chronic side effects. Intensity-modulated radiation therapy (IMRT) has emerged as an effective technique to deliver the full radiation dose to the tumor and regions at risk while reducing exposure of surrounding healthy tissues. However, the preservation of anatomy does not necessarily translate into the preservation of swallowing function.[9]

Mucositis induced by chemoradiation therapy or chemotherapy alone, edema, pain, thickened mucous saliva and hyposalivation, radiation dermatitis, and infection may all contribute to acute dysphagia. The use of epidermal growth factor inhibitors seems not to be associated with increased mucositis and acute dysphagia.[10]

By 3 months posttreatment, acute clinical effects have largely resolved, and normal swallowing function starts to return in most patients. Unfortunately, in head and neck cancer patients treated with chemoradiation, a continuing cascade of inflammatory cytokines triggered by oxidative stress and hypoxia may damage exposed tissues, and dysphagia may develop even years after the completion of treatment. Late sequelae that may contribute to chronic dysphagia include the following:

• Reduced capillary flow.
• Atrophy and necrosis.
• Lymphedema.
• Neuromuscular fibrosis leading to trismus and stricture formation.
• Hyposalivation.
• Infection.

Successful management of dysphagia requires the following:

• Interdisciplinary collaboration.
• Accurate and early diagnostic workup.
• Effective preventative and therapeutic strategies.
• An individual approach geared to unique patient characteristics.

Dysphagia- and aspiration-related structures have been identified, and minimizing radiation to these bystander tissues results in better swallowing outcomes.[11] Because hyposalivation affects swallowing function, strategies aimed at sparing salivary glands such as IMRT and the use of amifostine may improve swallowing outcomes.[12,13]

A predictive model for persistent swallowing dysfunction following chemoradiation therapy for head and neck cancer has been developed.[14] Early involvement of a speech and language therapist is critical to assess swallow function and aspiration risk and to generate a treatment plan that includes patient education and swallow therapy.[15] Cooperation with a dietician is important to ensure adequate and safe nutrition. Prosthodontic interventions may improve swallowing performance, and patients may benefit from psychological support.

Dysgeusia

Dysgeusia can be a prominent symptom in patients who are receiving chemotherapy or head/neck radiation.[16,17] Etiology is likely associated with several factors, including direct neurotoxicity to taste buds, xerostomia, infection, and psychologic conditioning. In addition, taste dysfunction can be associated with damage caused by graft-versus-host disease to the taste perception units. (Refer to the Graft-versus-Host Disease section of this summary for more information.)

Patients receiving chemotherapy may experience unpleasant taste secondary to diffusion of drug into the oral cavity. In addition, chemotherapy patients often describe dysgeusia in the early weeks after cessation of cytotoxic therapy. This symptom in general is reversible, and taste sensation returns to normal in the ensuing months.

By comparison, however, a total fractionated radiation dose higher than 3,000 Gy reduces acuity of sweet, sour, bitter, and salt tastes. Damage to the microvilli and outer surface of the taste cells has been proposed as the principal mechanism for loss of the sense of taste. In many cases, taste acuity returns in 2 to 3 months after cessation of radiation. However, many other patients develop permanent hypogeusia. Zinc supplementation (zinc sulfate 220 mg 2 times a day) has been reported to be useful in some patients; the overall benefit of this treatment remains unclear.[18];[19][Level of evidence: I]

Nutritional Considerations

Patients with head and neck cancer are at high risk for nutritional problems. Contributing to malnutrition are the following:[20]

• The malignancy itself.
• Poor nutrition before diagnosis.
• Complications of surgery, radiation therapy, and chemotherapy.

In cancer patients, loss of appetite can also occur secondary to mucositis, xerostomia, taste loss, dysphagia, nausea, and vomiting. Quality of life is compromised as eating becomes more problematic. Oral pain with eating may lead to selection of foods that do not aggravate the oral tissues, often at the expense of adequate nutrition. Nutritional deficiencies can be minimized by modifying the texture and consistency of the diet and by adding more frequent meals and snacks to increase calories and protein. Ongoing nutrition assessment and counseling with a registered dietitian should be part of the patient's treatment plan.[21]

Many patients who receive radiation therapy alone are able to tolerate soft foods; however, as treatment progresses, most patients must transition to liquid diets using high-calorie, high-protein liquid nutritional supplements, and some may require enteral feeding tubes to meet their nutritional needs. Almost all patients receiving concurrent chemotherapy and radiation therapy will become fully dependent on enteral nutritional support within 3 to 4 weeks of therapy. Numerous studies have demonstrated the benefit of enteral feedings initiated at the onset of treatment, before significant weight loss has occurred.[22,23]

Oral nutrition is reinstituted after treatment has concluded and the radiated site has adequately healed. Oral nutrition often requires a team approach. The assistance of a speech and swallowing therapist to assess for any swallowing dysfunction resulting from surgery or treatment is often necessary and beneficial in easing the transition back to solid foods. The number of tube feedings can be decreased as a patient's oral intake increases, with tube feeding being discontinued when 75% of a patient's nutrition needs are being met orally. Although most patients will resume adequate oral intake, many will continue to experience chronic complications such as taste changes, xerostomia, and varying degrees of dysphagia that can affect their nutritional status and quality of life.[20,21]

Fatigue

Cancer patients undergoing high-dose chemotherapy and/or radiation therapy can experience fatigue related to either the disease or its treatment.[24] These processes can produce sleep deprivation or metabolic disorders that collectively contribute to compromised oral status. For example, the fatigued patient will likely have impaired compliance with mouth care protocols designed to otherwise minimize risk of mucosal ulceration, infection, and pain. In addition, biochemical abnormalities are likely involved in many patients. The psychosocial component can also play a major role, with depression contributing to overall fatigue. (Refer to the PDQ summary on Fatigue for more information.)

References:

1. Jensen SB, Mouridsen HT, Reibel J, et al.: Adjuvant chemotherapy in breast cancer patients induces temporary salivary gland hypofunction. Oral Oncol 44 (2): 162-73, 2008.
2. Jensen SB, Pedersen AM, Vissink A, et al.: A systematic review of salivary gland hypofunction and xerostomia induced by cancer therapies: prevalence, severity and impact on quality of life. Support Care Cancer 18 (8): 1039-60, 2010.
3. Nguyen NP, Moltz CC, Frank C, et al.: Dysphagia following chemoradiation for locally advanced head and neck cancer. Ann Oncol 15 (3): 383-8, 2004.
4. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al.: Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 26 (22): 3770-6, 2008.
5. Logemann JA, Rademaker AW, Pauloski BR, et al.: Site of disease and treatment protocol as correlates of swallowing function in patients with head and neck cancer treated with chemoradiation. Head Neck 28 (1): 64-73, 2006.
6. Pauloski BR, Rademaker AW, Logemann JA, et al.: Pretreatment swallowing function in patients with head and neck cancer. Head Neck 22 (5): 474-82, 2000.
7. Kronenberger MB, Meyers AD: Dysphagia following head and neck cancer surgery. Dysphagia 9 (4): 236-44, 1994.
8. Platteaux N, Dirix P, Dejaeger E, et al.: Dysphagia in head and neck cancer patients treated with chemoradiotherapy. Dysphagia 25 (2): 139-52, 2010.
9. Mittal BB, Pauloski BR, Haraf DJ, et al.: Swallowing dysfunction--preventative and rehabilitation strategies in patients with head-and-neck cancers treated with surgery, radiotherapy, and chemotherapy: a critical review. Int J Radiat Oncol Biol Phys 57 (5): 1219-30, 2003.
10. Curran D, Giralt J, Harari PM, et al.: Quality of life in head and neck cancer patients after treatment with high-dose radiotherapy alone or in combination with cetuximab. J Clin Oncol 25 (16): 2191-7, 2007.
11. Eisbruch A, Schwartz M, Rasch C, et al.: Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 60 (5): 1425-39, 2004.
12. Sasse AD, Clark LG, Sasse EC, et al.: Amifostine reduces side effects and improves complete response rate during radiotherapy: results of a meta-analysis. Int J Radiat Oncol Biol Phys 64 (3): 784-91, 2006.
13. Büntzel J, Glatzel M, Mücke R, et al.: Influence of amifostine on late radiation-toxicity in head and neck cancer--a follow-up study. Anticancer Res 27 (4A): 1953-6, 2007 Jul-Aug.
14. Langendijk JA, Doornaert P, Rietveld DH, et al.: A predictive model for swallowing dysfunction after curative radiotherapy in head and neck cancer. Radiother Oncol 90 (2): 189-95, 2009.
15. Murphy BA, Gilbert J: Dysphagia in head and neck cancer patients treated with radiation: assessment, sequelae, and rehabilitation. Semin Radiat Oncol 19 (1): 35-42, 2009.
16. Bartoshuk LM: Chemosensory alterations and cancer therapies. NCI Monogr (9): 179-84, 1990.
17. Garrick R: Neurologic complications. In: Atkinson K, ed.: Clinical Bone Marrow and Blood Stem Cell Transplantation. 2nd ed. Cambridge, UK: Cambridge University Press, 2000, pp 958-79.
18. Silverman S Jr: Complications of treatment. In: Silverman S Jr, ed.: Oral Cancer. 5th ed. Hamilton, Canada: BC Decker Inc, 2003, pp 113-28.
19. Ripamonti C, Zecca E, Brunelli C, et al.: A randomized, controlled clinical trial to evaluate the effects of zinc sulfate on cancer patients with taste alterations caused by head and neck irradiation. Cancer 82 (10): 1938-45, 1998.
20. Robinson CA: Enteral nutrition in adult oncology. In: Elliott L, Molseed LL, McCallum PD, eds.: The Clinical Guide to Oncology Nutrition. 2nd ed. Chicago, Ill: American Dietetic Association, 2006, pp 138-55.
21. Kagan SH, Sweeney-Cordes E: Head and neck cancers. In: Kogut VJ, Luthringer SL, eds.: Nutritional Issues in Cancer Care. Pittsburgh, Pa: Oncology Nursing Society, 2005, pp 103-16.
22. Beer KT, Krause KB, Zuercher T, et al.: Early percutaneous endoscopic gastrostomy insertion maintains nutritional state in patients with aerodigestive tract cancer. Nutr Cancer 52 (1): 29-34, 2005.
23. Tyldesley S, Sheehan F, Munk P, et al.: The use of radiologically placed gastrostomy tubes in head and neck cancer patients receiving radiotherapy. Int J Radiat Oncol Biol Phys 36 (5): 1205-9, 1996.
24. Visser MR, Smets EM: Fatigue, depression and quality of life in cancer patients: how are they related? Support Care Cancer 6 (2): 101-8, 1998.

Psychosocial Issues

Oral complications of cancer, including oral mucositis [1] and salivary gland hypofunction/xerostomia,[2] are among the most devastating of both short- and long-term problems encountered by people with cancer because they affect eating and communication, the most basic of human activities. Patients with these problems can become withdrawn, socially avoidant, and even clinically depressed as a result of the difficulties and frustrations they encounter living with oral complications.

When psychotropic drug interventions are employed in the treatment of such patients, it is important that the drugs chosen will improve, or at least not worsen, their oral complications. For example, in the treatment of depression, highly anticholinergic drugs should be avoided in patients with xerostomia and salivary problems. (Refer to the PDQ summaries on Adjustment to Cancer: Anxiety and Distress and Depression for more information.)

Supportive care, including education and symptom management, are important for patients experiencing oral complications related to cancer therapy. It is important to closely monitor each patient's level of distress, ability to cope, and response to treatment. This approach provides a setting for the health professional to demonstrate concern for the patient's complications and to educate the patient and family caregivers. Comprehensive supportive care from staff and family can enhance the patient's ability to cope with cancer and its complications.

References:

1. Dodd MJ, Dibble S, Miaskowski C, et al.: A comparison of the affective state and quality of life of chemotherapy patients who do and do not develop chemotherapy-induced oral mucositis. J Pain Symptom Manage 21 (6): 498-505, 2001.
2. Langendijk JA, Doornaert P, Verdonck-de Leeuw IM, et al.: Impact of late treatment-related toxicity on quality of life among patients with head and neck cancer treated with radiotherapy. J Clin Oncol 26 (22): 3770-6, 2008.

Special Considerations in Pediatric Populations

Altered dental growth and development is a frequent complication in long-term cancer survivors who received high-dose chemotherapy and/or head/neck radiation for childhood malignancies.[1,2,3,4,5,6,7,8] Radiation doses as low as 4 Gy have been shown to cause localized dental defects in humans.[9,10]

Developmental disturbances in children treated before age 12 years generally affect size, shape, and eruption of teeth as well as craniofacial development:

• Abnormal tooth formation manifests as decreased crown size, shortened and conical shaped roots, and microdontia; on occasion, complete agenesis may occur.
• Eruption of teeth can be delayed, including increased frequency of impacted maxillary canines.
• Shortened root length is associated with diminished alveolar processes, leading to decreased occlusal vertical dimension.
• Conditioning-induced injury to maxillary and mandibular growth centers can compromise full maturation of the craniofacial complex.

Because the changes tend to be symmetric, the effect is not always clinically evident. Cephalometric analysis is typically necessary to delineate the scope of the condition.

The extent and location of dental and craniofacial anomalies largely depend on the age at which cancer therapy was initiated and the cancer regimen used. Children younger than 5 or 6 years at the time of treatment (particularly those who undergo treatment that involves concomitant chemotherapy and head and neck radiation) appear to have a higher incidence of dental and craniofacial anomalies than do older patients or those who undergo only chemotherapy.[11,12]

The role and timing of orthodontic treatment for patients who have transplant-related malocclusions or other alterations of dental growth and development are not fully established. The number of successfully managed orthodontic interventions appears to be increasing; however, specific guidelines for management, including optimal force and pace with which teeth should be moved, remains undefined. The influence of growth hormone relative to improved development of maxillary and mandibular structures is yet to be comprehensively studied. Such studies may well influence recommendations for orthodontic treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for further information.)

Management of oral complications in pediatric patients is additionally challenging because of the relatively limited research base directed to oral toxicities. New, comprehensive research studies are thus needed.

References:

1. Cohen A, Rovelli R, Zecca S, et al.: Endocrine late effects in children who underwent bone marrow transplantation: review. Bone Marrow Transplant 21 (Suppl 2): S64-7, 1998.
2. Dahllöf G, Barr M, Bolme P, et al.: Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 65 (1): 41-4, 1988.
3. Dahllöf G: Craniofacial growth in children treated for malignant diseases. Acta Odontol Scand 56 (6): 378-82, 1998.
4. Dahllöf G, Forsberg CM, Ringdén O, et al.: Facial growth and morphology in long-term survivors after bone marrow transplantation. Eur J Orthod 11 (4): 332-40, 1989.
5. Uderzo C, Fraschini D, Balduzzi A, et al.: Long-term effects of bone marrow transplantation on dental status in children with leukaemia. Bone Marrow Transplant 20 (10): 865-9, 1997.
6. Lucas VS, Roberts GJ, Beighton D: Oral health of children undergoing allogeneic bone marrow transplantation. Bone Marrow Transplant 22 (8): 801-8, 1998.
7. Dahllöf G, Heimdahl A, Bolme P, et al.: Oral condition in children treated with bone marrow transplantation. Bone Marrow Transplant 3 (1): 43-51, 1988.
8. Rosenberg SW, Kolodney H, Wong GY, et al.: Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. A review of 17 cases. Cancer 59 (9): 1640-8, 1987.
9. Fromm M, Littman P, Raney RB, et al.: Late effects after treatment of twenty children with soft tissue sarcomas of the head and neck. Experience at a single institution with a review of the literature. Cancer 57 (10): 2070-6, 1986.
10. Goho C: Chemoradiation therapy: effect on dental development. Pediatr Dent 15 (1): 6-12, 1993 Jan-Feb.
11. Näsman M, Forsberg CM, Dahllöf G: Long-term dental development in children after treatment for malignant disease. Eur J Orthod 19 (2): 151-9, 1997.
12. Hölttä P, Hovi L, Saarinen-Pihkala UM, et al.: Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer 103 (7): 1484-93, 2005.

Changes to This Summary (12 / 16 / 2016)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Editorial changes were made to this summary.

This summary is written and maintained by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the pathophysiology and treatment of oral complications of chemotherapy and head/neck radiation. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Supportive and Palliative Care Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Supportive and Palliative Care Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."

The preferred citation for this PDQ summary is:

PDQ® Supportive and Palliative Care Editorial Board. PDQ Oral Complications of Chemotherapy and Head/Neck Radiation. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/about-cancer/treatment/side-effects/mouth-throat/oral-complications-hp-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389320]

Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.

Disclaimer

The information in these summaries should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Managing Cancer Care page.

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More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website's Email Us.

Last Revised: 2016-12-16